TURNING DISCOVERIES INTO TREATMENTS FRONTIERS WINTER l 2018

PATHOLOGY FROM THE COCKPIT Bidding adieu (largely) to glass slides 1x

A Cancer Center Designated by the National Cancer Institute

THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER – JAMES CANCER HOSPITAL AND SOLOVE RESEARCH INSTITUTE UPFRONT The Director’s Perspective

Changing of the Guard

With the changing of the year comes a changing of the guard at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James). While we are saddened by the impending departure of former OSUCCC Director and James CEO Michael A. Caligiuri, MD, who in February will embark on a new WILLIAM FARRAR, MD RAPHAEL POLLOCK, MD, PhD career opportunity in California, Interim CEO, James Cancer Hospital Director, The Ohio State University Comprehensive Cancer Center we are also honored to have been chosen to guide Ohio State’s cancer program in pursuit of our shared into innovative cancer care and when mutated drives some of the vision of a cancer-free world. prevention strategies. deadliest forms of cancer—and The OSUCCC – James Through the combined efforts our researchers’ efforts to discover flourished under Dr. Caligiuri’s of our dedicated faculty, staff and an effective inhibitor to blunt its leadership, enjoying record volunteers, we intend to build oncogenic effects. You can also read financial performance, earning upon the outstanding reputation about our recently launched Digital the highest possible descriptor of the OSUCCC – James as a Program that will fully of “exceptional” during our two transformational cancer hospital digitize our anatomical pathology most recent NCI surveys, receiving that provides compassionate cancer services over the next 10 years. patient-satisfaction scores that rank care to the patients and families who Excitement is mounting at the among the nation’s highest, and turn to us for help. OSUCCC – James, and we thank gaining a reputation as one of the We offer evidence of our you for sharing in it by taking time most translational cancer hospitals commitment in this issue of to peruse this edition of Frontiers. in the country as we readily Frontiers. Here you can gain insight convert laboratory discoveries into the RAS oncogene—which

THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER – ARTHUR G. JAMES CANCER HOSPITAL AND RICHARD J. SOLOVE RESEARCH INSTITUTE

Interim CEO, James Cancer Hospital Deputy Director, OSUCCC Chief Financial Officer EDITORIAL BOARD WILLIAM FARRAR, MD PETER SHIELDS, MD JULIAN BELL Jennifer Carlson William Carson III, MD Director, The Ohio State University Distinguished University Professor Chief Communications Officer Stephen Chaykowski Comprehensive Cancer Center OSU Cancer Scholar and Senior Adviser MELISSA HALL Jeffrey Fowler, MD RAPHAEL POLLOCK, MD, PhD CLARA D. BLOOMFIELD, MD Melissa Hall Editor, Frontiers Electra Paskett, PhD, MSPH Senior Executive Director Medical Director of Credentialing DARRELL E. WARD, MS Christine Scarcello, MBA JEFF A. WALKER, MBA WILLIAM FARRAR, MD Nancy Single, PhD Darrell E. Ward, MS cancer.osu.edu

The OSUCCC – James invites you to be a member of our online community.

cancer.osu.edu facebook.com/thejamesosu twitter.com/thejamesosu youtube.com/osuthejames

02 Read Frontiers online or download an issue at http://cancer.osu.edu/Frontiers. FRONTIERS WINTER 2018 FEATURES

14 COCKPIT PATHOLOGY 24 BREAKING THE RAS CEILING promises to After more than 30 years of help pathologists focus more on research, there is still no effective diagnoses and consultations and RAS inhibitor, but OSUCCC – James less on chasing down glass slides researchers may change that

04 FRONTLINE 12 OF NOTE PRECISION CANCER Recent grants, awards and honors, new faculty and program developments Cancer medicine is in the midst of an exciting transition

06 BREAKTHROUGH 29 BENCH TO BEDSIDE CAR-T IMMUNOTHERAPY APPROVED KAMI MADDOCKS, MD A Phase I/II Study of the PD-1 Antibody ONALESPIB GLIOBLASTOMA Nivolumab in Combination With Lenalidomide in Relapsed/Refractory Non-Hodgkin A microRNA WITH MACRO POSSIBILITIES and Hodgkin miR-122 expression might predict survival of liver-cancer patients NSAIDs IMPLICATED 26 NEED TO KNOW Long-term anti-inflammatory drug use may increase cancer- EDITORIAL BOARD SOLID TUMOR TRANSLATIONAL related deaths for certain patients Jennifer Carlson SCIENCE SHARED RESOURCE William Carson III, MD UPDATED AML GUIDELINES Stephen Chaykowski Advances prompt release of new recommendations for Jeffrey Fowler, MD diagnosis, management of adult AML Melissa Hall Electra Paskett, PhD, MSPH ANTICANCER SYNERGY 27 JAMES UPDATE Christine Scarcello, MBA Two investigational antitumor agents work better together MEETING SPECIAL NEEDS TURNING CANCER DISCOVERIES INTO TREATMENTS against MPNST and FRONTIERS Nancy Single, PhD WINTER l 2018 Darrell E. Ward, MS IMPROVING PROGNOSTIC PROWESS New prognostic classification may help clinical decision-

making in glioblastoma PATHOLOGY FROM THE COCKPIT Bidding adieu (largely) to glass slides 1x VOICES FOR VACCINATION ON THE COVER: cancer.osu.edu Ohio State joins national call for HPV vaccination of Digital Pathology. cancer.osu.edu facebook.com/thejamesosu twitter.com/thejamesosu youtube.com/osuthejames Scanned uterine tumor section A Cancer Center Designated by the children to prevent cancer National Cancer Institute enlarged to 400x. See page 14. THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER – JAMES CANCER HOSPITAL AND SOLOVE RESEARCH INSTITUTE 03 FRONTLINE The Researcher’s Voice MOVING PRECISION CANCER MEDICINE INTO THE CLINIC This is an amazing time to be an cancer syndrome that increases oncologist. Cancer medicine is in the lifetime risk for colorectal and the midst of an exciting transition, other . But MSI also occurs shifting away from the - in spontaneous cancers, and strong based practice that we’ve known evidence suggests that up to 80 for decades and toward precision percent of patients with MSI- cancer medicine (PCM)—the use positive tumors might respond well of genomics to identify genes in to immunotherapy. patient tumors that we can target with . There is little data available for the prevalence of MSI in most Nurturing this evolution is the types of spontaneous tumors. At federal Cancer Moonshot Initiative, the same time, the growing use of which seeks to make a decade’s next-generation sequencing (NGS) worth of progress in five years. is making data available for tumor Key concepts that underlie the types not usually tested for MSI. Moonshot effort include “big data,” “data sharing” and “innovation.” This raises the need for tools that can quickly and accurately analyze At the OSUCCC – James, we are this data in multiple cancer types. making progress in all three areas in our attempts to help move PCM Fortunately, such tools are into the clinic. available. MANTIS (Microsatellite Analysis for Normal Tumor InStability) is a new algorithm BY SAMEEK ROYCHOWDHURY, MD, PHD, INTERPRETING BIG DATA designed to classify samples by MSI assistant professor in the Division of Medical Interpreting large sets of genetic status utilizing existing NGS data. at Ohio State and a member of the OSUCCC – James data is part and parcel of precision Translational Therapeutics Program cancer medicine. The ultimate Our team published a study in purpose for analyzing big data is to the journal Oncotarget showing identify the most effective therapy that MANTIS had the highest for our patients. overall sensitivity and specificity Recent research has shown that for detection of MSI status across the presence in tumor cells of an six different tumor types. It also alteration called microsatellite required less memory and had instability has important treatment faster run times. Next, we will apply implications. Microsatellites are this to data from the Oncology short strings of repeated DNA Research Information Exchange bases. If the number of repeats in Network to identify additional malignant cells differs from that patients with MSI, which could of nearby healthy cells, the tumor lead to a novel immunotherapy for is said to show microsatellite these patients. instability (MSI). DATA SHARING MSI is a surrogate marker for Our ability to identify the gene the silencing of key DNA repair mutations, or cancer variants, mechanisms. MSI testing is that drive tumor growth and commonly done when screening progression lies at the heart of for Lynch syndrome, an inherited precision cancer medicine. But

04 PRECISION CANCER MEDICINE FRONTLINE FRONTIERS WINTER 2018

“Through three active clinical trials at the OSUCCC – James, we are studying how patients respond to novel FGFR inhibitors.” doing so requires a common Several OSUCCC – James how the information could be useful language, standardized terminology researchers are working on the for developing innovative . and a level of description that problems of drug and radiation Through three active clinical trials facilitates their use in research and resistance. Our team recently led at the OSUCCC – James, we are their ready interpretation in clinical a study published in the journal studying how patients respond to practice. Molecular Cancer Therapeutics that novel FGFR inhibitors. demonstrated a mechanism by Currently, genomic information which and bladder cancer cells Clearly, there is no routine cancer. collected by many databases is develop resistance to a new class of Each patient is different, and described and shared differently, drugs called fibroblast growth factor each needs molecular testing. The which can create discrepancies, receptor (FGFR) inhibitors. Cancer Moonshot will focus our inconsistencies and information research efforts in ways that hasten gaps that make the clinical or Our findings in a laboratory the transition to precision cancer research use of variants difficult. model provide insights into how medicine, and that should produce For example, different terminology clinical trials for these agents could better outcomes for all cancer is often used to classify germline and be further developed to prevent patients. F somatic variants (see box). or overcome drug resistance, and Fortunately, progress is underway here, too. We contribute to the team effort of the Clinical Genome COMPARISON OF GERMLINE AND SOMATIC VARIANT TERMINOLOGY Resource (ClinGen), a national NIH initiative that represents 75 Germline Variants Evidence institutions. • Pathogenic • Very strong Recently, ClinGen published • Likely pathogenic • Strong guidelines in the journal Genome • Variant of unknown • Moderate Medicine that attempt to standardize significance • Supporting information about cancer variants • Likely benign that is collected and shared so that • Benign everyone is speaking the same language. Somatic Variants Evidence • Diagnostic • Prospective trials The guidelines suggest the use of • Prognostic • Retrospective trials at least 16 discrete data elements to • Predictive • FDA approval define a mutation. Standardizing these elements creates a common • Expert opinion language for uniformly describing • Case reports mutations and what they mean for • Preclinical patients. • Inferential

INNOVATION Different terminology is often used to classify germline and somatic gene variations. Germline variants may be classified according to levels of pathogenicity, while somatic Ultimately, we use NGS and variants are classified into biomarker categories. The supporting evidence also is analyze big data to determine the different for each. Evidence of pathogenicity for a germline variant may be based on best therapy for our patients. That published reports of high penetrance and be considered “very strong,” while supporting relates to another Moonshot goal: evidence for a predictive somatic variant could come from a large randomized trial developing ways to overcome or from preclinical laboratory data. The ClinGen initiative is working to reduce such cancer’s resistance to therapy. inconsistencies in variant terminology.

05 06 www. jamesline.com/go/frontiers The Frontiers ofCancer Research BREAKTHROUGH LYMPHOMA Certain AdultLymphoma Patients CAR-T ImmunotherapyApprovedfor James hematologist attheOSUCCC – MPH SAMANTHA JAGLOWSKI, MD, and kill onlyand cancerous kill those cells. ofsurface and cell the target then markersrecognize specific the on lab ina modified and re-trained to white cells, are which blood therapyThe patient’s a uses own adults with advanced lymphoma. therapy known as CAR-T for in use approved abreakthrough cancer e Food and Drug Administration (FDA) has remission.” with therapy this tend to stay in Patientsseen. have who success rate of patients those is yet to be 60 percent, and average the survival CAR-T, response the rate is nearly months,” says Jaglowski. “But with average is about overall survival six is about 26percent, and the For patients, these rate the of success next inthe line of treatment treatment. treatment responded to CAR-T of chemotherapy or astem cell had at failed least two rounds data showed trial linical that more than of half patients who medicine.” really epitome the of personalized is therapy “This trials. inclinical OSUCCC –James, tested who the MD, MPH, ahematologist at the cancer,” says Samantha Jaglowski, andreinfused go to work fighting alivingtherapy.Thistruly is It’s apatient’s own cells that are Th “ C “ as chemotherapy and radiation. traditional cancer treatments such oftenwith thanfewer sideeffects remission within afew months and patients achieving complete aglowski notes that CAR-T tends to work quickly, with many 1-800-293-5066 Referral Center toll free: The James Line New-Patient To refer apatient, please call James, visit cancer.osu.edu/cart. moreo learn about CAR-T and at trials OSUCCCclinical the – . of treatment-resistant childhood FDA-approvedalso for a rare type CAR-T therapy.therapy The is currently country the offering e OSUCCC –James is one of only ahandful of centers across J T Th

Certain AdultLymphoma Patients CAR-T ImmunotherapyApprovedfor combination with temozolomide. effective at improving in survival blood-brain and barrier was most n animal models of glioblastoma agent(GBM), the crossed the invasion and migration. proliferation,cancer survival, cell tumors. This, in turn, reduced stem cells obtained from patient in glioma lines cell and inglioma endothelial growth factor receptor proteinssurvival such as AKTand reducedwhich expression of cell- s study showed that onalespib blocked HSP90 activity, thanhigher innormal cells. HSP90 expression 10times can be conformation. In cancer cells, HSP90 to achieve functional damage-response proteins require number of receptor and DNA- into form. functional their Alarge made proteinnewly fold molecules alespib inhibits aprotein HSP90, that amolecule called helps tumor treatment. chemotherapy for used drug brain- combined with temozolomide, a andbarrier is more effectivewhen lasting, crosses blood-brain the that targeted the inhibitor is long- – James. The findings suggest by researchers at OSUCCC the preclinical studies of glioblastoma e targeted therapy onalespib has shown effectiveness in Treatment forGlioblastoma Onalespib maybeanEffective GLIOBLASTOMA I Thi On Th 1-800-293-5066 Referral Center toll free: The James Line New-Patient To refer apatient, please call Cancer Research averaging 16-18months. incurable, with overall survival in2017.Itexpected remains with more than cases 12,000new lioblastoma is most the common form of brain cancer, glioblastoma,”diagnosed he says. effectivepatients in with newly standard therapy is safe and onalespib incombination with that determine whether will trial on results the Based of this study, we have generated aclinical researcher at OSUCCC the –James. at Ohio State and aclinician- Divisionthe of Neuro-Oncology MBBS, professor and director of investigator Vinay Puduvalli, therapy for GBM,” says principal ancould be exciting new chemotherapeutic temozolomide, and that, incombination with than other HSP90 inhibitors, blood-brainthe better barrier findingsOur suggestthat onalespib can efficiently breach Published in the journal the in Published G “ “ Clinical Clinical James. researcher attheOSUCCC – Stateandaclinician- at Ohio ofNeuro-OncologyDivision professor anddirector ofthe VINAY PUDUVALLI, MBBS, BREAKTHROUGH

FRONTIERS WINTER 2018

07 www. jamesline.com/go/frontiers BREAKTHROUGH The Frontiers of Cancer Research

LIVER CANCER A microRNA With Macro Implications

miR-122 expression might predict survival of liver-cancer patients

A molecule called regulating cholesterol and lipid microRNA-122 (miR-122) is metabolism. critical for regulating liver-cell “We want to understand metabolism and for suppressing how miR-122 regulates liver liver-cancer development. A study metabolism and suppresses cancer led by researchers at The Ohio State development, and to identify University Comprehensive Cancer common targets in humans and Center – Arthur G. James Cancer mice that may be involved in HCC Hospital and Richard J. Solove development,” says co-principal Research Institute (OSUCCC investigator and OSUCCC – James – James) and at Rockefeller researcher Kalpana Ghoshal, PhD, University’s Howard Hughes associate professor of pathology. Medical Institute shows that miR- “That knowledge is critical for determining whether this molecule KALPANA GHOSHAL, PHD 122 interacts with thousands of genes in liver cells. Levels of this should be developed as a possible associate professor of pathology molecule often drop during liver- therapeutic agent for liver cancer.” cancer development, and the study Ghoshal and her colleagues also found that when this happens, conducted their study using a the expression of certain cancer- mouse model that lacked miR- promoting genes goes up. 122, along with normal mice; liver The findings could one day help cancer tissues and normal liver doctors better predict survival tissues from nine HCC patients; in liver cancer patients and help and data from 373 HCC patients determine whether miR-122 should in The Cancer Genome Atlas Liver be developed as an anticancer drug. Hepatocellular Carcinoma dataset. The researchers sought to The findings significantly extend biochemically (rather than the number of miR-122 binding computationally) define all miR- sites identified by earlier studies 122 target sites in the liver and because the methods used by the hepatocellular carcinoma (HCC), investigators identified sites that the most common form of liver other techniques miss, Ghoshal cancer, and to learn which target adds. (Note: One gene can have genes were critical for liver-cancer multiple microRNA target sites.) development or progression. miR- 122 is found almost exclusively in Published in the journal Molecular liver cells, where its role includes Cell cancer.osu.edu

08 BREAKTHROUGH FRONTIERS WINTER 2018

ENDOMETRIAL CANCER A microRNA With Macro Implications NSAIDs Implicated

Long-term anti-inflammatory drug use may increase cancer-related deaths for certain patients

Regular use of over-the-counter data suggests that inhibition of non-steroidal anti-inflammatory through NSAID use drugs (NSAIDs) such as aspirin and plays a role in that process,” says ibuprofen is associated with greater Theodore Brasky, PhD, co-lead risk of dying in patients diagnosed author of the study and a cancer with type 1 endometrial cancers, epidemiologist with the OSUCCC – according to a new population- James. based study led by researchers at “This study identifies a clear the OSUCCC – James. association that merits additional In this observational study, a research to help us fully understand multi-institutional team of cancer the biologic mechanisms behind researchers sought to understand this phenomenon,” Brasky adds. the association of regular NSAID “Our finding was surprising use and the risk of dying from because it goes against previous endometrial cancer among a cohort studies that suggest NSAIDs can THEODORE BRASKY, PHD, of more than 4,000 patients. They be used to reduce inflammation co-lead author of the study found that regular NSAID use and reduce the risk of developing and a cancer epidemiologist was associated with a 66-percent or dying from certain cancers, like with the OSUCCC – James increased risk of dying among colorectal cancer.” women with type 1 endometrial Researchers point out that cancer, a typically less-aggressive information about specific dosages “There is increasing evidence form of the disease. and NSAID use after was that chronic inflammation is The association was statistically not available in the current study, significant among patients who which represents a significant involved in endometrial cancer reported past or current NSAID limitation. use at the time of diagnosis, but it risk and progression, and recent was strongest among patients who Published in the Journal of the data suggests that inhibition of had used NSAIDs for more than 10 National Cancer Institute years in the past and had ceased use inflammation through NSAID use prior to diagnosis. NSAID use was plays a role in that process.” not associated with mortality from typically more aggressive type 2 cancers. “There is increasing evidence that chronic inflammation is involved in endometrial cancer

risk and progression, and recent cancer.osu.edu

09 10

cancer.osu.edu ACUTE MYELOID LEUKEMIA “These guidelines are guidelines an“These important update ofthecurrentupdate andwidely managing AML, forconstructing managing AML, clinical trials and forpredicting outcomes ofAML patients.” used recommendations for adviser fortheOSUCCC –James State;cancerscholarOhio andsenior Distinguished University Professor at CLARA D.CLARA BLOOMFIELD, MD, diagnosis, management ofadultAML diagnosis, Advances prompt release ofnewrecommendations for Updated AMLGuidelines clinical trials.”clinical AML patients and designing recommendations for managing and replace will 2010ELN the standard new the be will of care co-chaired panel. the “They patients,” says Bloomfield,who for predicting outcomes of AML andconstructing trials clinical for managing AML,for and recommendations widely used important update of current the for OSUCCC the –James. cancer scholar and senior adviser at as Ohio State serves also who Distinguished University Professor Clara D. Bloomfield, MD, a paper’sThe senior author was published Blood. journal inthe LeukemiaNet (ELN)and were issued by European the adults. acute myeloid leukemia (AML)in for diagnosis the and treatment of opinion-based recommendations and expert- evidence-based has released updatedexperts “These guidelines are“These an The recommendations An international panel of

agents. development of novel antileukemic residual and disease, by the tests and tests for minimal detecting by development the of genetic new and genomic causes of disease, the by insights new into molecular the recommendations was prompted leukemia. of myeloid and acute Health Organization classification include updated newly the World trials. clinical category for progressive for disease status,disease and aproposed oncategory residual minimal based categories, aproposed response include ELNgenetic revised American Cancer Society. 10,600 of according them, to the 21,400 Americans year per and kills Published in the journal Blood Bloomfieldsays updatingthe ELN The recommendations also The updated recommendations Adult AMLaffects an estimated Research Institute at NCH. inThe Cancer and Blood at Center the for Childhood (NCH) and a principal investigator at Nationwide Children’s Hospital /Oncology and BMT is divisionCripe, also who chief of resistant to chemotherapy,” says More importantly, MPNST is it is leading the cause of death. cancer predisposition disorder, neurofibromatosis 1, a genetic cancer, but for patients with James. a researcher at OSUCCC the – PhD, aprofessor of and senior author Timothy Cripe, MD, agentsthese individually,” explains that have shown susceptibility to two difficult-to-treat sarcomas neuroblastoma are these because combination inMPNST and (MPNST) and neuroblastoma. sheathperipheral tumor nerve models in malignant of efficacy combination increases antitumor demonstrates that in use their However,trials. study anew as monotherapies inearly clinical shown some antitumor efficacy HSV1716—have separately and oncolytic the herpesvirus aurora inhibitor Akinase alisertib against peripheral nerve sheath tumors andneuroblastoma Two antitumoragentsworkinvestigational better together Anticancer Synergy PEDIATRIC CANCER “MPNST is arare pediatric “We investigated this Two investigational agents—the OncoTarget .” e s a c e h t other studies, we don’t that’s think virotherapy, but on data based from immunotherapeutic effects the of second phase, downstream the possible that it could inhibit the is impacted,” says. Cripe “It’s innateHSV1716 because immunity helps the phase of myeloid-derived suppressor cells. accumulation of intratumoral inhibitedalisertib virus-induced tumors. The also teamfound that and slowed clearance virus from production virus increased peak cytotoxicity. also Alisertib cellsuninfected to alisertib sensitivityincreased the of study.this Particularly, HSV1716 increase antitumor the in effect likely worked synergistically to 1-800-293-5066 Referral Center tollfree: The James New-PatientLine Published in the journal “Our study shows that alisertib saysCripe many mechanisms To please call refer apatient,

these agents individually.”these that have shown susceptibility to sarcomas two difficult-to-treat neuroblastoma because these are combination in MPNST and “Wethis investigated James and aresearcher attheOSUCCC – professor ofPediatrics State atOhio TIMOTHY CRIPE, MD, PHD, BREAKTHROUGH FRONTIERS

WINTER 2018 11 cancer.osu.edu BRAIN CANCER Improving Prognostic Prowess New prognostic classification may help clinical decision- making in glioblastoma New research shows that taking “Our study has established molecular variables into account and independently validated a will improve the prognostic novel molecular classification classification of the lethal brain of glioblastoma, perhaps the cancer called glioblastoma (GBM). most aggressive of all human Led by researchers at the malignancies,” says principal OSUCCC – James, the study found investigator Arnab Chakravarti, that adding significant molecular MD, professor and chair of the biomarkers to the existing GBM Department of Radiation Oncology classification system improves at Ohio State and co-director the prognostic classification of of the Brain Tumor Program. GBM patients who have been “The revised model offers a more treated with radiation and the drug accurate assessment of prognostic temozolomide. groups in GBM patients who have The current model, used been treated with radiation and internationally for nearly two temozolomide. decades, is based on clinical “We believe that incorporating ARNAB CHAKRAVARTI, MD, variables alone. It was created c-MET- and MGMT-protein professor and chair of the Department of before the introduction of expression enhances the prognostic Radiation Oncology at Ohio State and temozolomide, which along with classification of glioblastoma co-director of the Brain Tumor Program radiation is the current standard of patients over and above the care for GBM. traditional clinical variables, The new, refined classification and that it will improve clinical was derived using samples from 452 decision-making,” says Chakravarti, “We believe that incorporating GBM patients treated with radiation who also holds the Max Morehouse c-MET- and MGMT-protein and temozolomide. It includes Chair in Cancer Research at Ohio such key molecular markers as State. “Furthermore, inclusion of expression enhances the MGMT-protein and c-MET-protein the MGMT protein provides insight prognostic classification of expression, along with such clinical into the potential for resistance to glioblastoma patients over and variables as age, performance status, radiation and temozolomide.” extent of resection and neurological above the traditional clinical function. Published in the journal JAMA variables, and that it will improve The researchers validated the Oncology model in an independent group of clinical decision-making.” 176 patients. cancer.osu.edu

12 low across country. the cancers, vaccination rates remain oropharyngeal and genital andwarts, may help prevent cancer andagainst genital cervical toclose 100percent protection Although HPVvaccines provide each year United inthe States. associated cancers are diagnosed approximatelyrise; 39,000HPV- associated cancers continue to ccording to CDC, the incidence rates of HPV- Prevention (CDC). Centers for Control Disease and recommendations from the supporting recently revised centers to issue ajoint statement (NCI)-designated cancer National Cancer Institute has again united with 69 the OSUCCC the –James(HPV), humanthe papillomavirus to aneed improveecognizing national vaccination rates for cancer. protects against of types several understanding that vaccine this from , and parents not of strong recommendations to barriers improvedey vaccination rates include alack complete series. three-dose the older than 14should continue to adolescents and young adults least sixmonths apart, and that of 9-valent the HPVvaccine at age 15should receive two doses guidelines CDC e new recommend that children under HPV-RELATED CANCERS children toprevent cancer Statejoins callforHPVOhio national vaccination of Voices for Vaccination A R K Th 1-800-293-5066 Referral Center tollfree: The James New-PatientLine Cancer Research journal the in Published 2015. November in Center of Texas MDAnderson Cancer a summit hosted at The University majorthe recommendation from jointe original statement, published inJanuary 2016,was improving vaccination rates. collectiveactiontowardidentify research, practicesand best discuss of national summits to share new have organized acontinuing series o overcome barriers, these NCI-designated cancer centers community,” she adds. HPV-associated cancers inour change to reduce burden the of Thisthe is HPV vaccination,No. andbarrier to 1 it must Control Program. where Cancer the leads she also atsciences OSUCCC the –James, associate director for population Paskett,says Electra PhD, MSPH, public prevention health vaccines,” dootherHPV vaccine like they consistently recommending the communitymedical simply isn’t appropriate vaccination, and the child’s healthcare provider for recommendationsParents of their rely heavily on the To please call refer apatient, Th T “ “

vaccines.” healthpreventionother public the HPV vaccine like they do isn’t consistently recommending communitysimply the medical appropriate and vaccination, child’s healthcare provider for recommendations oftheir “Parents rely heavily onthe attheOSUCCCsciences –James associate director forpopulation ELECTRA PASKETT, PHD, MSPH,

BREAKTHROUGH FRONTIERS WINTER 2018

13 cancer.osu.edu OF NOTE Recent Recognition of OSUCCC – James Physicians and Researchers

GRANTS

RICHARD FISHEL, PhD, professor of Cancer THE JAMES CANCER HOSPITAL AND SOLOVE RESEARCH Biology and Genetics, has received a five-year, INSTITUTE earned a 2017 Press Ganey Guardian of $1.8 million renewal grant (CA067007) from the Excellence Award for Patient Experience in inpatient care. National Cancer Institute (NCI) to understand in Press Ganey, a recognized leader in measuring patient detail the mechanism of DNA mismatch repair. experience, presents this award to organizations that have achieved a 95th percentile or higher overall rating on their patient-experience surveys in a given year.

THE SURGICAL INTENSIVE CARE UNIT AT THE OSUCCC – JAMES has received a three-year, silver level Beacon Award for Excellence from the American Association of Critical-Care Nurses (AACN) for exceptional patient care and professional practice. The AACN includes more than 500,000 ROSA LAPALOMBELLA, PhD, assistant professor of Internal acute and critical care nurses and more than 235 chapters Medicine; ROBERT BAIOCCHI, MD, PhD (center), associate worldwide. professor in the Division of Hematology; and JOHN C. BYRD, MD, professor in the Division of Hematology, have received THE OSUCCC – JAMES presented the 22nd Herbert and a five-year, $2.3 million NCI grant (CA214046) titled “Targeted Maxine Block Memorial Lectureship Award for Distinguished Therapies for Richters Transformation.” Achievement in Cancer to Mary-Claire King, PhD, the American Cancer Society Professor of Medicine and Genome Sciences LEAH PYTER, PhD, associate professor of at the University of Washington. The OSUCCC – James , has received a five-year, $1.78 million extends the annual $25,000 award to an internationally NCI grant (CA216290) to investigate whether prominent scientist who presents a lecture about his or her chemotherapy alters the makeup of the gut research. The award is supported by the annual Herbert J. community in ways that cause chemotherapy- Block Memorial Tournament, a golf outing sponsored by the related cognitive problems. Block family of Columbus.

QI-EN WANG, PhD, assistant professor of , has received a five-year, $2.3 million FACULTY AND PROGRAMS grant (CA211175) from the National Cancer JEFFREY PATRICK, PHARMD, is the new Institute titled “Averting Recurrent and Resistant director of the OSUCCC – James Drug Ovarian Tumors.” Development Institute, which helps accelerate promising anticancer agents discovered by Ohio State researchers through pharmaceutical AWARDS AND HONORS development. Patrick formerly was chief scientific officer at New Haven Pharmaceuticals in Connecticut. JOHN C. GRECULA, MD, FACR, professor of Radiation Oncology, has been inducted as a DENIS GUTTRIDGE, PhD, professor of Cancer Fellow of the American College of Radiology Biology and Genetics, has been named (FACR). The ACR considers recognition as a associate director for basic research at the fellow to be one of the highest honors it can OSUCCC – James. In this role, Guttridge bestow on a radiologist, radiation oncologist or coordinates basic science across the five medical physicist. OSUCCC – James research programs and facilitates existing and new collaborative efforts. MICHAEL KNOPP, MD, PhD, professor of Radiology, has received a 2017 Ohio State JOANNA GRODEN, PhD, professor of Cancer University Distinguished Scholar Award, Biology and Genetics, has been named which recognizes exceptional scholarly director of the Pelotonia Fellowship Program, accomplishments by senior professors and which enables Ohio State students in any younger faculty who have demonstrated great discipline and at all levels to conduct cancer scholarly potential. research with guidance by faculty mentors.

14 OF NOTE

FRONTIERS WINTER 2018

JEFFREY VANDEUSEN, MD, PhD, a medical DAVID O’MALLEY, MD, associate professor in the oncologist with a focus on breast malignancies, Division of , was appointed has been named associate director for to the Ovarian Task Force representing NRG community network relations at the OSUCCC – Oncology. James. VanDeusen is an assistant professor in the

Division of Medical Oncology at Ohio State. FLOOR BACKES, MD, assistant professor in the Division of Gynecologic Oncology, was appointed CLAIRE F. VERSCHRAEGEN, MD, has been to the Uterine Task Force representing the appointed director of the Division of Medical Southwest Oncology Group (SWOG). Oncology at Ohio State and associate director for translational research at the OSUCCC – James. She holds the Diane Nye and Michael , Rayden Chair in Innovative Cancer Research and JOHN HAYS, MD, PhD assistant professor in the was appointed to the serves as a professor of . Verschraegen came to Division of Medical Oncology, Ovarian Task Force representing SWOG. Ohio State from the University of Vermont Cancer Center.

JAVIER GONZALEZ, MD, has joined the cancer program as an assistant professor of Neurological Surgery. He specializes in neuro-oncology and has a clinical and research interest in neuro- AWARDS AND HONORS . He came to Ohio State from West Virginia University. JOHN C. BYRD, MD, a Distinguished University ALLAN ESPINOSA, MD, has joined the cancer Professor at Ohio State, where he co-leads the program as an assistant professor in the Division Leukemia Research Program at the OSUCCC – of Medical Oncology. His clinical and research James, is the most recent recipient of the Leukemia interests include neuroendocrine and thyroid & Lymphoma Society’s (LLS) prestigious Return of cancers. Espinosa came to Ohio State from Cary the Child Award. The LLS established this national Medical Center, Northern Maine Medical Center award in 1986 to honor individuals who have devoted their careers and Millinocket Regional Hospital. to blood cancer research and whose national and international leadership within the oncology and biomedical communities has THE OHIO STATE UNIVERSITY has an agreement with Nanobio helped develop treatments for blood cancers, thereby improving Delivery Pharmaceutical Co. Ltd. for $1.4 million to establish a survival rates. Byrd was selected for his work on developing the Center for RNA Nanotechnology and for cancer drug ibrutinib and his leadership in the LLS’s Beat AML (acute research. The director of the center is Peixuan Guo, PhD, myeloid leukemia) initiative. professor in the College of at Ohio State. ERICA BELL, PhD, assistant professor-clinical in the Department of Radiation Oncology at Ohio LEADERSHIP ACTIVITIES AND State, is the recipient of the 2017 American Society APPOINTMENTS for Therapeutic Radiology and Oncology (ASTRO) Senior Investigator Basic/Translational Research ARNAB CHAKRAVARTI, MD, chair and Award. Bell identified MGMT promoter methylation as professor of Radiation Oncology and director of a key mediator of outcome and treatment resistance in anaplastic the Brain Tumor Program, has been appointed astrocytomas based on prospective National Cancer Institute to the NCI’s Board of Scientific Counselors. He cooperative group studies. will help guide NCI program planning in radiation oncology and neuro-oncology. TRAINEE RECOGNITION Members of the gynecologic oncology team at the OSUCCC – James have been appointed to NCI steering committee or task JUAN BARAJAS, a doctoral student in the force roles: laboratory of OSUCCC – James researcher KALPANA GHOSHAL, PhD, has been awarded a DAVID COHN, MD, professor and director of Howard Hughes Medical Institute (HHMI) Gilliam the Division of Gynecologic Oncology, was Fellowship for Advanced Study. HHMI Gilliam appointed to the Uterine Task Force representing Fellowships recognize exceptional doctoral students NRG Oncology, a clinical cooperative group. He is who have the potential to be leaders in their fields also chair of NRG Oncology’s Cancer Care Delivery and the desire to advance diversity and inclusion in the sciences. cancer.osu.edu Research (CCDR) committee and represents the organization on NCI’s CCDR Steering Committee. 15 Pathology From the Cockpit Digital pathology promises to help pathologists focus more on diagnoses and consultations and less on chasing down glass slides

BY KENDALL POWELL

Until recently, when a pathologist wanted to review the prior slides from a complex case with an expert pathologist or colleague, he or she had to request the glass slides from the archives and wait hours to days for the slides to arrive so that they could be shared. But that is changing at Ohio State. In May 2017, The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) initiated a comprehensive Digital Pathology Program that will fully digitize anatomical pathology services over the next 10 years. The new system will enable OSUCCC – James pathologists to sit at a large viewer and, with a few clicks, call up a patient’s digitized and annotated specimens, along with his or her , complete with molecular biomarker tests and genomic data. The program uses whole-slide imaging (WSI) technology, which scans entire glass pathology slides and converts them into digital images. “With that technology, a computer becomes a ,” says Anil Parwani, MD, PhD, MBA, who heads the program as director of Digital Pathology at the OSUCCC – James. The system provides fully Above is a microscope slide with a thin slice of tumor that has been stained to bring out automated end-to-end pathology cellular details. The tissue will be scanned under a high-throughput slide scanner to produce a workflow and a bank of ultra- digital image of the tissue and its cellular structures. The bar code on the left links the tissue to fast scanners that are used to the patient’s molecule test results and medical record, which the pathologist can review while digitize both current and past glass examining the tissue section in a digital cockpit, shown on page 16.

16 misdiagnosis could be associated couldmisdiagnosis be indicating risk that ahigh a vitro III in categorized WSI scanners as Class U.S. Food and Administration Drug and In other diseases? 2009,the ut used could slides digital be for diagnosis of primary the cancer more widespread. consultations.became Their use from anywhere, vastly up speeding simultaneously analyze slides digital more, multiple people could was lost, broken or faded. What’s slides only tothat find a slide hunting down archived glass imagese digital were easily stored and transferred—no more research. slidesdigital for teaching and files. Universitiesbegan using could accommodate large image had technology 2000s,the y the improved, and desktop computers slides their directly.viewing more quickly and accurately by were skeptical; could work they and slow to upload. Pathologists were low quality, enormous insize SI was introduced technology earlyin the 1990s,but images the physicians. and report findings treatingto images for second opinions diagnostic images, share pathology slides anddigitized other cockpits”pathology to view –JamesUCCC pathologists sit soon atwill desktop “digital- slides. pathology B Th B W OS diagnostic devices, diagnostic devices, made from slides. glass comparediagnoses with those studies to show how slide digital researchers large run validation will says. In addition, OSUCCC –James Parwani slidedigital diagnoses, concordance and glass between and by studies that show high at concern is addressed being by improvements technology inthe adopt that atechnology was not pathologists remains reluctant to And, he says, his generation of forimages.used radiology digital format like DICOM the standard field should a standard choose systems difficult. the says Parwani formats, making transfers between or example, different scanners different use WSI image says. arena inits is still infancy,” Parwani hurdlesther remain, also. “Digital clinical inthe pathology image. slide was converted to adigital information was lost aglass when A leading question was whether morbiditywith high or mortality. Th F O

FEATURE: DIGITAL PATHOLOGY image onyour iPhone.” them is much like viewing an move seamlessly andviewing very now, good the images reality,“In thetechnology is OSUCCC –James director Pathology ofDigital atthe ANIL PARWANI, MD, PHD, MBA, FRONTIERS WINTER 2018

17 cancer.osu.edu 18 cancer.osu.edu the patient’s medical record. medical the patient’s The screen atleft displays the thecenter screengross tumor; displays the screen thedigitized tumor section; at right displays PathologyDigital Director Anil Parwani, examines adigitized tissue section MD,PhD,MBA, in adigitalcockpit atTheJames. ince his recruitment from Universitythe of Pittsburgh in not have seen.” otherwise of things that shespectrum might got really excited. It extended her from difficult cases China, and she love with it. She was consulting on anothertechnology try. “She fell in but her he to persuaded give the wouldpathology slow her down, center thought who that digital a senior pathologist at another iPhone,” he says. Parwani recalls much an like viewing image on your seamlessly and is them viewing now, good very In reality, images the move is technology the thousandsscan of old slides. convert and to pathology digital of and time the cost required to nearly 20years ago. They are wary mature first they when tested it S “ image has abarcode thatOnce aslide is stores digitized, the storage. and ordering slides from those finding priorsamples from patient a paperwork to patient slides or manually managing matching cases, 10-15 percent of time their estimates that pathologists spend information management. He pathology.digital First is efficient highlightsthree arwani major advantages inadopting University Wexner Medical Center. of Pathology at The Ohio State Frankel, MD, professor and chair into space,” vital this says Wendy OSUCCCcould the –James lead someone who already experienced – James. “We brought as inAnil same excitement at OSUCCC the 2016, Parwani has created that “ P reeing image the from aphysical meansslide also that multiple emailed to colleagues anywhere. on other the hand, easily can be of asample. Entire slides, digital but provide they only alimited view photomicrographs to colleagues, Pathologists have long sent advantage to pathology. digital of imageEase sharing is another attached to slides. digitized the biomarkers and gene sequencing, record, including moleculardata on with apatient’s electronic medical referred hass idea been to as “digital the cockpit,” pathology at my fingertips.” patientassociated with aparticular theputs materialall “This information systems,” he says. and integrated be it will into our ofall patient’s the information, F Thi research, consultations andallaspects ofpathology.” education, will digitalpathology create forprimary solution anend-to-end diagnosis, “At we’re State, Ohio creating Pathology aDigital Center thatat its core states. slidesglass to colleagues inother says it about takes aweek to ship it’s to easy do,” notes Parwani, who a second opinion on something if research. “You are more likely to get presentations and collaborating on consultations, tumor-board checks, training students, quick an image for quality assurance people can simultaneously review , such analysis could quantitate an immunostained cancer marker currently done by pathologist. the tumor measurements that are perform tedious counts cell and Computer-assisted analysis could ally, slides digitized allow remarkable analytical possibilities. patients sooner.” information more quickly and see digitizing slides, we’ll receive that slides,”pathology says Kipp. “By previous images and radiology patients here until we have their region or country. the “We can’t see referrals from other of parts the Itdiagnoses. facilitate also will second opinions or evenprimary hospitals to submit images for e explains that it may one day or allow smaller more rural officer the at –OSUCCC James. andpatient chief nursing services MSN, RN,executive director, an efficient way,” saysKris Kipp, to to bring others our in expertise center, we pathology can digital use center and an medical academic As acomprehensive cancer Or Fin H “

cockpit. Center, houses which atraining Pathology Digital the Innovation State, training their with begins adopt technologies. these At Ohio course, on how well pathologists systems are integrated. And, of analysis tools and information WSI scanners, image storage, image e success of pathology digital ultimately on depends how well confirmed pathologist.by a would which diagnoses, be slides to generate preliminary do afirst-passscreening patientof algorithms to used could be then of atype breast cancer. These slides of, say, hundreds of samples developed using of sets digitized ventually, says Kipp,diagnosing algorithms auto- might be paperwork and other tedious tasks.” from counting cells, chasing andmaking diagnoses me frees spend more as time aphysician “Digital enables pathology me to and disordered,” says Parwani. or areas identify that are chaotic that are larger size, than aparticular such as mitoses or positive nuclei The computerand efficientlycanquantitate more quickly rare events consultations of and aspects all diagnosis, research, education, solutionpathology for primary createwill an end-to-end digital PathologyWe’re Center that at its core creating aDigital more objectively than apathologist. such as HER2for breast cancer Th E “ “ —Anil Parwani, MD,PhD,MBA FEATURE: DIGITAL PATHOLOGY Digital pathology is a very is avery pathology Digital Pathology scanning center. aspirate samples to Digital the frozen and sections fine-needle are already sending slides with and OSUCCC –James pathologists It’s year one of a10-year project, pathology,” says Parwani. 1-800-293-5066. Referral Center toll-free: The James New-PatientLine .” e m i t for right the patient at right the helping us make right the diagnosis precision cancer medicine by “Digital can pathology promote prognosis and treatment, she says. how physicians assess apatient’s and it ultimately may improve providing more timely diagnoses, at includes improving qualitythe of patient care by it can help us doour jobsbetter.” pathologists,” cannot pathology Digital replace Frankel stresses, “but guide prognosis and treatment. other patient and outcome data to images merged can be also with than slides. glass accessed The and more archived easily and diagnostic and research purposes, he points out that digitized slides are more annotated easily for missions.” center three of with all those can help us as an medical academic care, teaching and research, and it inclinical is practiced pathology “It has potential the to change how innovative way to go,” Frankel says. “ To please call refer apatient, Th “ S F

FRONTIERS WINTER 2018

19 cancer.osu.edu Breaking the RAS Ceiling After more than 30 years of research, there is still no effective RAS inhibitor, but OSUCCC – James researchers may help change that

BY DARRELL E. WARD In 2014, Ohio State cancer “RAS oncogenes are of immense halting cancers driven by these researchers were deep into a study importance in many cancers,” says mutations.” investigating a question related to principal investigator Albert de la In fact, nearly one-third of microRNAs in melanoma when Chapelle, MD, PhD, Distinguished cancers contain a RAS mutation, they made an astonishing discovery. University Professor in the but the gene that is mutated varies Analysis of their data revealed that Molecular Biology and Cancer with cancer type. For example, RAS an infamous oncogene called NRAS Genetics Program at The Ohio State mutations are present in: encodes five proteins, not just one University Comprehensive Cancer 95 percent as was thought. Center – Arthur G. James Cancer of pancreatic cancers (KRAS) Hospital and Richard J. Solove 45 percent Research Institute (OSUCCC – of colorectal cancers (KRAS) James). “Virtually thousands of labs ALBERT 35 percent are working on various aspects of of lung cancers (KRAS) DE LA CHAPELLE, RAS, so our findings could have MD, PHD, important implications.” 15 percent professor of Medicine The three-member family of RAS of AML (NRAS) and the Leonard genes—KRAS, HRAS and NRAS— 15 percent J. Immke Jr. and has been notoriously difficult to of melanoma (NRAS) Charlotte L. Immke understand and to target. After 10 percent Chair in Cancer more than 30 years of research, of bladder cancers (HRAS) Research there is still no effective RAS In some cases, RAS mutations inhibitor, earning these proteins make cells resistant to therapy, and a reputation as “undruggable.” their presence in tumor cells can Agents that are approved for RAS- influence treatment decisions. mutant tumors target downstream OSUCCC – James researchers molecules, but these inhibitors have are studying NRAS and KRAS in been largely ineffective, especially as WILLIAM particular to better understand and single agents. CARSON III, MD, treat these cancers. “RAS mutations drive some of professor of Medicine In healthy cells, RAS proteins the most deadly types of cancer, help regulate the transduction of and they do so by activating signals triggered by hormones, many signaling pathways that cytokines and growth factors. All facilitate cancer-cell growth and three proteins have GTPase activity progression,” says William Carson and are involved in transmitting III, MD, professor of Surgery signals involved in cell growth, and associate director for clinical proliferation and migration. research at the OSUCCC – James. Normally, RAS proteins receive “Targeting one downstream signals that cause them to switch molecule isn’t enough to block the between an active state (bound to action of this cancer-causing gene guanine triphosphate, or GTP) and because cancer cells often develop an inactive state (bound to guanine alternate pathways and escape diphosphate, or GDP). the block. Inhibiting RAS directly In cancer cells, mutated RAS would be much more effective in is locked into its active state

20 are completely unknown.” but origins the of other mutations carcinogensthe incigarette smoke, mutations have attributed been to lung-cancer-associated KRAS atGenetics Ohio State. “Certain andGenetics of and Cancer Biology assistant professor of Molecular researcher E.Burd, Christin PhD, cancer type,” says OSUCCC –James are preferentially mutated ineach it is unclear why RAS certain expressed throughout body, the three proteins RAS All so are widely proliferation, and invasion. survival and continuously promotes We discovered four the OSUCCCthe –James. cancer scholar and senior to adviser at as Ohio State serves also who a Distinguished University Professor researcher Clara D. Bloomfield, MD, Program, and OSUCCC –James State’s Medical Scientist Training Eisfeld, MD, of is who part Ohio Chapelle,la Carson, Ann-Kathrin isomers beganwith astudy by led de ofdiscovery four the NRAS new ANOTHER RAS 13 and 61. positions protein: inthe codons 12, utations three genes inall predominantlyoccur inonly three • sequence; three proteins RAS ll share over 80percent of amino their acid • e three genes are located on three different chromosomes; • and For surprises. example: family bulges closet with oddities oncogenes discovered, to be and its

“ “ The researchthat the led to M A Th RAS was one of earliest the SURPRISE NRAS genes

worldwide.” signaling and intensely so studied genes are central so to oncogenic for 30years, eventhoughRAS the gone unnoticed by researchers of four isoforms of NRAS were that surprised existence the in AMLpatients,” Eisfeld says. “We and differential NRAS at impact the of NRAS isoforms ‘by accident’ looking when RNA box, Alternative (see Splicing, splicing of NRAS the are produced through alternative isoformcalled 1.Isoforms 2to 5 just one the known protein, now proteins, NRAS occurring not gene can produce five naturally researchers found that NRAS the National Academy of Sciences. The reported 2014findings the ey the of Proceedings journal in the Th Characteristics oftheFiveNRAS Splice-Variant Proteins previously 2: NRAS protein 1: Thepreviouslyknown NRAS isoform component exons, 2-5 a littleofexon 5 5: Part ofexon 2and only 4: Exons 2and5 little ofexon 4 3: Exon 2anda exon, 3b(red) Containsa unknown unknown with four FEATURE: BREAKINGTHERAS messenger expression mutations mutations had 76 20 208 189 amino acids) (number of Protein length 40

pg. 28). pg. e five NRAS proteins differ in published its structure inthe melanoma cells. The researchers aggressivehighly behavior in just 20amino acids and triggers NRAS box, Characteristics of(see Five the intracellular location and effects human malignancies and intheir size, inexpression levels indifferent Th Notably, isoform 5consists of Splice-Variant Proteins). mRNA components Cancer Research ChairEndowed in Pace III William Greenville and OSUCCC –James, advisersenior tothe cancer scholar and University Professor, Distinguished BLOOMFIELD, MD, CLARA D. Nucleus Cytoplasm Nucleus Cytoplasm Cytoplasm location Cellular FRONTIERS CEILING WINTER 2018

21 cancer.osu.edu journal Protein Science. “We are full,” Duggan says. target BRAF-mutant tumors, but for hopeful that our discovery will go She found that after exposing melanoma patients with an NRAS- beyond being a surprising biological BRAF-mutant melanoma cells to mutant tumor, therapeutic options observation and have implications the drug, expression of isoform 2 are limited. for overcoming the ‘undruggable’ shoots up, when formerly it had “A person can do most everything attribute of NRAS,” Eisfeld adds. been undetectable. “We hypothesize right and still be diagnosed with The researchers’ efforts to that this is an escape mechanism for highly metastatic disease,” she says. elucidate the functions of each the cells, and it may explain why the “We know that sunlight contributes isoform are also yielding insights disease recurs after a great response to melanoma, but we don’t know into isoform 2. to the anti-BRAF agent. the fundamental cause of the disease, Megan Duggan, PhD, a graduate “When we knocked down which makes it very hard to fellow in Carson’s lab, examined isoform 2 in a mouse model, the prevent.” BRAF-mutated melanoma cells animals became responsive again The idea that evolutionary exposed to vemurafenib, a drug to vemurafenib. These results selection might be the key to approved for the treatment of in the animal model were very identifying the Achilles’ heel of BRAF-mutated melanoma. encouraging,” she says. NRAS-melanoma began with “Patients using the drug have another surprising Ohio State UNLOCKING RAS MUTATIONS fantastic responses, but then a few observation. Burd and her weeks later the disease returns in Christin Burd wants to learn why colleagues designed a mouse particular RAS mutants are common model in which they can switch in some cancers and not others. on an NRAS gene mutation in KATHRIN-ANN For example, why NRAS is by far just the melanocytes of mice. EISFELD, MD, the most frequently mutated RAS They generated one mouse model of Ohio State’s gene in melanoma, and why these containing an inducible NRAS Medical Scientist mutations seem to always appear in mutation at codon 12 and another Training Program location 61. This is contrary to other with a mutation at codon 61. cancer types like acute myeloid “We were shocked to learn that, leukemia, where NRAS is also of the mice with an inducible selectively mutated, but typically at codon-12 NRAS mutation, none codon 12 or 13. developed melanoma, but when we “There appears to be evolutionary activated the codon 61 mutation, 80 selection for particular RAS percent of the mice spontaneously mutations in each cancer type,” developed tumors,” Burd says. Burd says. “The question is, can we This experiment, published better understand why these specific in the journal Cancer Discovery, MEGAN mutations evolve in each tumor was the first to suggest that the type such that drugs can be made DUGGAN, PHD, cancer-causing potential of NRAS to target only their cancer-inducing OSUCCC – James codons 12, 13 and 61 mutants were functions?” graduate fellow different, and it led to an “Aha!” To begin her work, she is focusing moment for Burd, who reasoned on melanoma, a cancer type for that the findings might offer a way which more than 10 new therapeutic to discover vulnerabilities specific regimens have been FDA-approved to each NRAS-mutant cancer type. since 2011. Unfortunately, not one of She hypothesized that forcing an these drugs directly targets mutant NRAS codon-61 mutant, which NRAS, the second most common causes melanoma, to behave like genetic alteration in melanoma, after a codon 12 mutant, which doesn’t BRAF mutations, Burd explains. cause melanoma, could prevent “We have drugs that directly cancer formation or shut down

22 such abig problem that we can’t other tissues,” Burd says. “RAS bone marrow, colon the and many melanoma, but brain, inthe the RAS helpwill us better understand It’s manyso possibilities. These models incredibly exciting to have RAS aiming to understand role the of with colleagues around world the tissue, she plans to share mice these urthermore, these because mutations activated can be inany each can or cannot drive melanoma. of mutants, these determining why examine and compare properties the and 61.She and herthen team will mutations to codons 12,13 localized containing distinct,inducible NRAS developing nine mouse models Award. Using funds, she is these foundation’s prestigious Innovator firstthe ever Ohioan to receivethe Foundation and as was selected Damon Runyon Cancer Research pathways, critical these o identify Burd proposed her novel to idea the NRAS differentthan that treatto needed melanoma may completely be for apatient with NRAS from inAML.Thus, those the drug in melanoma may different be NRAS critical the says. “Furthermore, we that believe growth is completely new,” Burd The idea targetingof mutation-pathways specific to stopcancer to stop melanoma inits tracks. NRAS that inhibiting only subset of asmall NRAS to completely shut down mutant field,” says.she While others aimed This approach was drastically differentfrom ongoingthe in tactics tumor growth. “ F T “ “ as acancer driver not only in inother tumor types. -mutant AML.” functions would sufficient be activity, Burd hypothesized -driven pathways -mutant -mutant is is

homologous end-joining.” breaks by amechanism non- called repairthe of DNA double-strand KRAS because work suggests that it happens understood,” Williams says. “Our but mechanism the is not well radioresistance tumors, inthese suggest that KRAS Evidence fromand laboratory emerging studies data inhumans mutation. cancer patients have an active KRAS patients and 25percent of lung 45 percent of colorectal cancer of patients, treatment, and about 95percent bout of half patients with cancer undergo during damaging agents. to radiation and other DNA- mutations inKRAS are working to understand how Oncology, and his laboratory team associate professor of Radiation occurs, andoccurs, mutated KRAS “During DNA that period, repair arrest,”cell-cycle Williams explains. hit withCells radiationDNA sustain damage and go then into 53BP1. cells called break DNA repair inKRAS protein involved indouble-strand work implicates awell-characterized Moremeeting. specifically,their for RadiationSociety Oncology e researchers presented their findingsinitial the 2016 at American RADIATION RESISTANCE types.” answers for RAS all to end melanoma, but to provide ourall, ultimate is goal not just with scientific the community. After come from sharing models these am extremely for hopeful what will it to tackle onexpect our own, and I “ A Terence M.Williams, MD, PhD, “ Th mutations heighten

mutations foster cause resistance FEATURE: BREAKINGTHERAS -mutant cancer seems seems -mutant -mutant

and mutant the because form proteine KRAS difficult is so to target of because its size small ITSELF? WHY NOT TARGET KRAS downstream of KRAS into potential pathways to target DNA damage and provide insight themselves from radiation-induced verall, findings their suggest KRAS how KRAS- mutated cancer cells.” work effectively, in especially shownbeen to help make radiation says. “Inhibiting has MEKkinase to facilitate DNA repair, Williams signaling pathway MEKkinase the therapy.”to survive division and growth, enabling them repair, tumor cells can resume cell accelerate that process. After proper to hijack 53BP1 the pathway to Th O KRAS mutations activate also -mutated cells rescue . PHD, WILLIAMS, MD, TERENCE M. BURD, PHD, CHRISTIN E. Oncology of Radiation associate professor Genetics of Molecular assistant professor FRONTIERS CEILING WINTER 2018

23 cancer.osu.edu 24 cancer.osu.edu protein synthesis. It referstoaregulatedprocessthathappensinthecellnucleusduring Alternative splicingenablesasinglegenetocodeformultipleproteins. ALTERNATIVE SPLICING Illustrations byAnthonyBaker have differentproperties or cellfunctions. proteins (isomers)calledMASH, ASH, AS andSASH, eachofwhich could for aproteincalledSMASH, alternative splicingmightproducevariant that mRNAresultsindifferentproteins.Forexample, ifageneweretocode removed andsplicedtogetherduringtheeditingstep. Thetranslationof During alternative(ordifferential)splicing,different mRNA sequencesare together. sequences arespliced removed, andtheremaining Certain genesequencesare Next, themRNAisedited. messenger RNA(mRNA). is transcribedtoproduce the informationinagene During proteinsynthesis, becomes aproteinmolecule. a chainofaminoacidsthat information istranslatedinto read byribosomes,andthe the cellcytoplasm,whereitis The maturemRNAthenenters move field the forward. OSUCCC –James are helping to resistance, investigators at the overcome RAS anddependencies testing to drugs therapy, to definingcancer-specific discovered isoforms changes during how expression of newly the RAS targeting is changing how about we think datanew emerging field, inthe Burd says. “And that, along with are building upon one another,” advanced cancer. rectal trametinib inpatients with locally radiation and MEKinhibitor the operative 5-fluorouracil (5-FU), evaluating combination the of pre- (ClinicalTrials.gov NCT01740648) helped to lead aphase trial Iclinical mutant cancers after radiation pathways that sustain KRAS- inhibition would block DNA the e preclinical data from Williams’ lab suggesting that MEK effective inhibitor.” wouldwhich likely make an GTP out of binding the pocket, findingthat a molecule kicksthe says. “No one yet has in succeeded binds strongly so to GTP, Williams RAS improve outcomes for patients with that target proteins these and ultimately novel devise strategies I am confidentthat thewill field It creativity, take and will collaboration,” hard work Burd adds, “but areas these All of UNDRUGGABLE? WILL RAS signsinitial of activity.” safe and tolerable, and that there are farso show that combination the is phase IItrial,” he says. “Our results inalargertrial multi-institutional That is nearlytrial done, and apply wethen will to continue the Th “ “ “ -mutant tumors.” REMAIN . From understanding -induced radiation RAS F research research BENCH TO BEDSIDE From theLaboratory tothePharmacy who arewho not candidates for HDT/ transplantcell (ASCT). For patients (HDT) followed by autologous stem curative option therapy is high-dose s oftencurable front-with patientsDLBCL relapse. The only line therapy, but 30-40 percent of HD. in subsets of patients with NHLand effective and have minimal toxicity for need the meet therapies that are RATIONALE: from combined the agents. resultshistology ingreater benefit NHL aparticular determine whether with assessing response, help it will follicular lymphoma (FL).Along and(DLBCL) relapsed/refractory large diffuse B-cell lymphoma phase IIstudy inrelapsed/refractory an expansion cohort inHDand a relapsed/refractory NHL,with with nivolumab inpatients with ofII dose lenalidomide combined ordose recommended the phase and maximum tolerated study determine safety, the will I/II, open-label, single-institution STUDY phase DESIGN:This to agents the alone. used when better to than be responsesexpected responses to combination the are prognostic marker profile. Patient (HD),regardlessdisease of their lymphoma (NHL)or with Hodgkin patients with non-Hodgkin B-cell safe,be tolerable and effective in of nivolumab and lenalidomide will HYPOTHESIS: The combination Disease Lenalidomide in Relapsed/Refractory Lymphoma Non-Hodgkin andHodgkin A Phase Study I/II ofthePD-1 Antibody Nivolumab in Combination With NHL i This trial will help patients are treated with HDT/ Asdisease. inNHL,relapsed factors relapse or have refractory but patients prognostic with poor hows five-year progression- percent afterfront-line therapy, (PFS) rates survival free of 61-89 anti-CD20 antibodies. of rituximab and other monoclonal significantly improved withthe use incurable, although outcomes have therapy. FLis usually considered and requiredisease intensive patients transform to aggressive Aboutsurvival. 30percent of FL treatment and shortened experience relapse quickly or are to refractory others require immediate therapy, long remissions with treatment; therapy for years several and mosts the common achieve indolent NHL. Some patients require no responses and unacceptable toxicity. salvage regimens provide short ASCT due to age or comorbidities, HD s FL i assent. assent. of ageorolder, andmustbewilling andabletoprovidewritteninformedconsent/ chemotherapy; hashadatleast onepriortherapy, includingpriorASCT; 18years or lymphocytepredominant HD thatisrelapsedorrefractoryafteratleastoneprior macroglobulinemia); Burkittlymphoma transformedtoDLBCL;confirmedclassical MCL, MZL,lymphoplasmacytic lymphoma/Waldenstrom Eligibility: PI: gov identifier: Trial no.: ClinicalTrial AT AGLANCE Email: Phone: 614-293-3196

KAMI MADDOCKS,MD [email protected] Histologically confirmed B-cell NHL (DLBCL, FL, HistologicallyconfirmedB-cellNHL(DLBCL,FL, NCT03015896 OSU-16167

primarily myelosuppression and rash. well tolerated with toxicity, minimal and inrelapsed/refractory HD. It is indolent relapsed/refractory NHL aggressiveactivity inboth and enalidomide is an immune modulator that shows clinical prolonged PFS. ASCT, and about 50percent have NHL and HD. patients with relapsed/refractory and duration of responses in response rates, depth of remission, with lenalidomide might improve suggestsreclinical evidence that nivolumab incombination appetite, nausea and pruritis. fatigue, rash, diarrhea, decreased frequent adverse events include hematologic malignancies. The most early in signsother of efficacy HDand hasrefractory shown ivolumab is aPD-1 inhibitor that is approved inrelapsed/ L P N BENCH TO BEDSIDE FRONTIERS WINTER 2018 25 cancer.osu.edu 26 cancer.osu.edu NEED TO KNOW At theOSUCCC –James Shared Resource Solid Tumor Translational Science assays during trials. clinical provide coordination seamless of Laboratory Shared Resource to – James Trials Clinical Processing and work they with OSUCCC the provide experts both TTSSR assay development and data analysis, trials. biomarkers of as part phase Iand II identificationthe or validation of managing correlative studies for investigators indesigning and assists OSUCCC –James clinical SharedScience Resource (STTSSR) S Solid The Tumor Translational studies; require correlative laboratory at trials clinical Ohio State that companies that are conducting pharmaceutical and biomedical – James investigators and elps develop strategic partnerships OSUCCC between • laboratory space; perform correlative studies but lack clinician investigators want who to for valuableparticularly service specimens, a of clinical-trial as acentral laboratoryerves for acquisition the and processing n addition, STTSSR: the • Research Shared Resource. Tumorthe Solid Translational researchsenior associate with XIANGLOU (TOM) LIU, PHD, fusion. gene BRAF or BRAF mutated with thyroidiodine-refractory cancer patients with advanced or metastatic randomized involved phase IItrial provided The by STTSSR. the translationalthe research services (OSU-12064) offers an example of uid-biopsy assay developed OSUCCC –James trial clinical by for STTSSR the arecent standards. Improvement Amendments (CLIA) Laboratory under Clinical determine treatment, are performed andselection stratification, to that assays required for patient orks closely with OSU the Pathology Core Facility to ensure •

H S I A liq W

STTSSR include:STTSSR providedlaboratory by services the translational research studies. Other planse STTSSR to this use liquid-biopsy capability infuture progression. response to treatment and tumor throughout treatment could predict samples at collected and baseline tumor-cell DNA from patient mutationsBRAF incirculating to evaluate levels whether of aliquid-biopsyused technique a designed e STTSSR correlative study that for trial this translational-science. shared-resources/solid-tumor- osu.edu/research-and-education/ or more information about visit https://cancer. STTSSR, the uminex multiplex protein assays. • immunoflourescence; dentifying signaling pathways using and PCR; llele-specific • • ustom-designed targeted sequencing panels; • RNA,ifying miRNAfrozen and samples; protein from or cells, blood fresh circulatingifying miRNA • from plasma, and urine saliva; •

Th Th F L I A C Pur Pur cause of death for age the group. of awareness that cancer is aleading and diagnoses clinical lack missed feelings of invincibility, delayed or care, inadequate insurance coverage, tumor biology, less access to clinical groups. The reasons include unique YA has not improved survival at samethe rates as it has for other age eachyear. diseases these and about 10,000of dieof them are with cancer diagnosed annually, 15-39. An estimated 72,000AYAs young adults (AYAs), people aged of adolescents killer disease and prevention, cancer is No. the 1 espite advances inearly detection, treatment and Meeting SpecialNeeds return-to-work issues throughout psychologic, fertility, and family and to addresssocial, services specific to provide additional AYA- expand our program, we hope Lustberg adds. “As we further We strive to address unique the ofneeds AYA the population,” OSUCCC –James. director for survivorship at the Lustberg, MD, MPH, medical research programs,” says Maryam through dedicated treatment and lives after diagnosis, and so we do help live them longer and better These youngpatients are our future, and we are working to of unique this patient population. Columbus to diverse the meet needs Nationwide Children’s Hospital in partnership at with specialists e OSUCCC –James survivorship program works in back on track and to have children. date, to get careers and finances find friends,it difficult to to make is completed, AYA survivors can treatments. Finally, once treatment make it difficult toidentify suitable participationlow clinical-trial adults, and alack of research and same cancers inchildren and older lso, cancers inAYAs may be biologically differentthan the JAMES UPDATE A D “ “ Th A Equally important,Equally we provide implementedcan be aftertreatment. fertility-preservation choices that option,” Appiah says, “we discuss pretreatment measures are not an freezing and banking.“When sperm that include and egg embryo assisted reproductive technologies providers to offer pretreatment and infertility ppiah and Jenkins collaborate reproductivewith local patients. reproductive cares health, for male and inmale aspecialist assistantclinical professor of ppiah provides care for female patients; Lawrence Jenkins, MD, age 39. program follows survivors through through AYA the age 50;otherwise, through age 45and survivors male follows female AYA survivors concerns,fertility program the to fertility,” their says Appiah. For treatmentrisk their regimen poses We and male both female see patients at diagnosis to the discuss University Wexner Medical Center. and at Gynecology The Ohio State professor of clinical Appiah,Leslie MD, associate program, says oncofertility specialist ptimizing reproductive potential is an important of goal the cancerthe continuum.” A A “ O life as cancer survivors.” maximize qualitythem their of treatment begin they and help reach young these people before ofe goal program, the Lustberg and Appiah add, to “is osteoporosis. density,mineral leading to canmen, reduce they bone- endurance. In women both and dysfunction, andsexual reduce canmen, cause they fatigue and in engage activity; insexual flashes and an inability to changesthese canto lead hot reproductive organs. In women, and radiation injuryto the as ovarian or testicular failure that affect quality of life, such e program addresses also late effects cancerof treatment treatment.” pregnancy either during or after implicationsthe of an unplanned appropriately and understand AYA patients contraceptives use says. “We want sure to be that of oncofertility,”aspect Appiah a widely under-appreciated ontraception is also important. “Contraception is aftertreatment.” arewho not at risk of infertility reassurance for patients those Th Th C NEED TO KNOW for survivorship directormedical MPH, LUSTBERG, MD, MARYAM health male reproductive and aspecialist in professor ofUrology clinical assistant JENKINS, MD, LAWRENCE and Gynecology clinical ofObstetrics associate professor LESLIE APPIAH,MD, From left: FRONTIERS WINTER 2018

27 www. jamesline.com/go/frontiers THE OHIO STATE UNIVERSITY Non Profit Org. COMPREHENSIVE CANCER CENTER – U.S. Postage ARTHUR G. JAMES CANCER HOSPITAL AND PAID RICHARD J. SOLOVE RESEARCH INSTITUTE Columbus, OH 300 W. 1Oth Avenue Permit No. 711 Columbus, OH 43210-1240

PELOTONIA FUNDING ALLOCATIONS WILL SUPPORT STUDENT & FACULTY CANCER RESEARCH

New allocations of funding from Pelotonia, an annual grassroots bicycle tour that raises money for cancer research at Ohio State, will support eight projects by teams of OSUCCC – James scientists and 42 projects by Ohio State students working in the labs of faculty mentors. The faculty-team projects will be funded by the OSUCCC James’ Intramural Research Program (IRP), which receives extensive Pelotonia support. IRP funding, which includes Idea Grants and other awards, goes to teams of scientists who competitively propose groundbreaking studies that will generate data to help them compete later for larger grants from external sources such as the National Cancer Institute. The newest IRP projects, collectively funded at $1.14 million, range from evaluating targeted therapies for thyroid cancer and immunotherapy treatment approaches in breast cancer, acute myeloid leukemia and brain tumors, to laboratory research aimed at understanding cancer stem cell differentiation in ovarian cancer. Over the past seven years, 108 OSUCCC – James research teams have received Pelotonia-supported IRP awards totaling $11.1 million. Each award provides research support for two years. The Pelotonia Fellowship Review Committee at the OSUCCC – James recently awarded 42 fellowships totaling $2 million to students from multiple disciplines and at various levels of scholarship, including 26 undergraduates, 14 graduates and two postdoctoral fellows. The undergraduates will receive funding for one year; graduates and postdoctoral fellows will receive funding for two years. Since the fellowship program began, it has allocated $13 million for 436 awards to 205 undergraduates, 128 graduates, 97 postdoctoral researchers and six medical students.

INSIDE THE NEXT FRONTIERS

The OSUCCC’s New Leader Raphael Pollock, MD, PhD, a globally respected cancer , researcher and educator, is the new director of The Ohio State University Comprehensive Cancer Center (OSUCCC). Pollock was recruited to Ohio State in 2013 from MD Anderson Cancer Center, where he had worked for 31 years and held several leadership positions. A story in the next Frontiers will introduce Pollock and relate his vision for propelling Ohio State’s cancer program forward.