Stewardship Report

Presented to: The H Foundation December 2015 Our Appreciation

Dear Friends of The H Foundation:

The Robert H. Lurie Comprehensive Cancer Center of is deeply grateful for The H Foundation’s extraordinary support over the past 15 years. Since 2002, The H Foundation has raised and donated more than $3 million to advance research at the Lurie Cancer Center. In turn, the Lurie Cancer Center has been able to leverage these generous philanthropic funds into more than $50 million in private and government grants for cancer research projects that bridge basic science and clinical care. I am delighted to share this report featuring the faculty members who have received Bridge Awards, Pilot Awards, and other support during 2014-2015. Your giving continues to impact the investigations of our highly dedicated scientists as they work together to find a cure for cancer. Over the years, The H Foundation’s partnership has helped us to stimulate and enable creative, novel research that has led to fundamental new discoveries, accelerating progress towards achieving new diagnostics and treatments for cancer. At the Lurie Cancer Center, we are developing programs that bridge basic science and clinical care and that will establish Chicago as a global leader in the delivery of personalized cancer treatment. Established in 1974, the Lurie Cancer Center is recognized as one of just 45 National Cancer Institute (NCI)-designated “comprehensive” cancer centers in the country for its dedication to the highest standards of cancer research, patient care, education, and community outreach. Our center is a founding member of the National Comprehensive Cancer Network and the Big Ten Cancer Research Consortium. Through our affiliations with four Chicago hospitals, we treat more than 15,000 new cancer cases each year. The Lurie Cancer Center is enjoying remarkable growth, and we are so grateful to The H Foundation for its longstanding commitment. Your philanthropy is helping us to catalyze high-impact cancer studies and accelerate the pace of breakthroughs that will ultimately benefit patients for years to come. From the bottom of my heart, thank you again for your extraordinary dedication and support of our research efforts at the Lurie Cancer Center.

Sincerely,

Leonidas C. Platanias, MD, PhD Jesse, Sara, Andrew, Abigail, Benjamin and Elizabeth Lurie Professor of Oncology Director, Robert H. Lurie Comprehensive Cancer Center of Northwestern University

2 H Foundation Pipeline Awards 2014-2015 The H Foundation’s support helped to provide seed funds to promote early translational research. These funds are meant to support projects with innovative drug or product development ideas that would otherwise be difficult to fund because of early stage or lack of preliminary data. The following awards were bestowed in November 2014.

Mary Hendrix, PhD President and Director, Stanley Manne Children’s Research Institute Professor, Robert H. Lurie Comprehensive Cancer Center of Northwestern University

“Targeting nodal signaling in tumor cells to suppress aggressive cancer” The Centers for Disease Control and Prevention identify melanoma as the fastest growing cancer in the world. Metastatic melanoma is the leading cause of skin cancer deaths in the United States. Despite advances in the field, the reference therapy for patients diagnosed with metastatic melanoma is still the same chemotherapeutic agent that was first approved for treatment in the 1970’s, and is not effective in targeting drug resistant melanoma cells with properties. Therefore, to address a critical clinical need, Dr. Hendrix is performing a priority, proof-of-concept study with significant translational relevance for patients. The study is testing the effects of a newly developed and characterized 3D1 Nodal function-blocking monoclonal antibody as a therapy for metastatic melanoma, which will specifically target drug-resistant melanoma cells with stem cell properties that express Nodal. The results generated so far indicate that treatment of metastatic melanoma cells with the novel 3D1 antibody leads to suppression of tumor growth. In addition, Dr. Hendrix and her colleagues have developed the first detection assay for Nodal in patient blood samples, which will form the foundation for monitoring Nodal expressing cancers and selecting patients for Nodal-targeted therapy. The data generated from this innovative study will be used to support the rationale for bringing this therapy to an early phase clinical trial and to develop a diagnostic test to select melanoma patients who would benefit from anti-Nodal therapy. Dr. Hendrix and her team’s observations describing the translational potential of the 3D1 Nodal function-blocking monoclonal antibody will be published in the journal Oncotarget in 2015.

Sui Huang, MD, PhD Associate Professor of Cell and Molecular Biology Richard Green, MD Professor of Medicine-Gastroenterology and Hepatology

“Development of MEAN as an effective chemotherapeutic against hepatocellular carcinoma” Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide and is reaching epidemic proportions in the United States, with the incidence of HCC in America tripling over the past three decades. Since chemotherapy is relatively ineffective for HCC, the development of highly-effective and less toxic chemotherapeutic agents for HCC is essential to improving the survival of patients with this common, highly lethal form of cancer. Drs. Huang, Green, and their colleagues have recently developed a small molecule, 6-methoxyethylamino-numonafide (MEAN), which has shown to be effective against metastatic tumor markers in mice. It has high potential as a candidate for further development into an anti-HCC chemotherapeutic drug. This study aims to further develop MEAN to make it Investigational New Drug (IND)–ready.

3 In addition to the studies accomplished with funds from The H Foundation, Drs. Huang and Green have made further progress comparing the anti-tumor growth properties of MEAN with sorafenib, the only FDA-approved drug against hepatocellular carcinoma. A manuscript describing their findings is currently in review for publication.

Teresa K. Woodruff, PhD Director, Women’s Health Research Institute; Chief, Division of Obstetrics and Gynecology-Fertility Preservation; Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology; Professor in Obstetrics and Gynecology-Fertility Preservation, McCormick School of Engineering, Medical Social Sciences and Medicine-Endocrinology

“Activin antagonists for treatment of cachexia” Half of all patients with cancer lose some body weight, with up to 30 percent of all cancer deaths being related to significant cancer-related cachexia and muscle wasting. Cachexia is known as general physical wasting with loss of weight and muscle mass due to a disease. Cancer-related cachexia is a major concern in the management of most late-stage cancers and is the acute cause of death in many of these patients. Because activin is one of the molecules that drives muscle wasting, a focused effort on the development of a small molecule antagonist of activin signaling is a vitally important endeavor. This project aimed to develop new sets of drug-like activin antagonists to make these suitable for subsequent development into pre-clinical leads.

The novel compounds that Dr. Woodruff and her group synthesized through The H Foundation pipeline award were a critical component of an invention disclosure that was recently submitted to Northwestern University as the first step towards patenting this class of molecules. This new intellectual property will give our scientists a greater chance of partnering with external organizations, such as pharmaceutical companies, who can help drive our discoveries towards the clinic. The group’s efforts to screen and test compounds led to a publication in the Journal of Medicinal Chemistry. In addition, Dr. Woodruff submitted a National Institutes of Health grant application this past June to continue supporting this work. Dr. Woodruff and her colleagues continue to test the new compounds. Their hope is to identify one or more compounds, which have suitable characteristics for testing in animal models of cancer cachexia.

Leonidas C. Platanias, MD, PhD Jessica Altman, MD Associate Professor of Medicine-Hematology/Oncology

“Optimization of Mnk-eIF4E inhibitors for the treatment of malignancies” Acute myeloid leukemia is a very heterogeneous disease with many patients facing a poor outcome—especially those who cannot tolerate high-dose chemotherapy. Drs. Platanias and Altman’s work is focused on developing new therapeutic strategies for myeloid leukemias that can enhance clinical outcomes in patients. Specifically, their laboratory has shown that chemotherapy as well as mTOR inhibitors can induce the MNK pathway, which allows the leukemia cells to continue to proliferate. Therefore, targeting of the MNK pathway is important in order to prevent relapse and/or resistance to current therapies in leukemia patients.

Drs. Platanias and Altman have been working with the Medicinal Chemistry and High Throughput Analysis Laboratory cores at Northwestern to identify Mnk1 inhibitor compounds and then modify them with the goal of developing drugs that can be advanced into the clinic. They have identified several new inhibitors and have synthesized many new compounds in

4 their preliminary hit-to-lead optimization. The funds from The H Foundation were used to improve the potency and drug-like properties of lead Mnk1 inhibitors.

H Foundation Bridge Awards 2014-2015 Bridge awards provide up to $20,000 of support for competing renewals of National Cancer Institute-sponsored R01 research studies that were not fully funded. The following bridge project was awarded in December 2014.

Carole LaBonne, PhD Arthur A. Anderson Research/Training Professor of Molecular Biosciences Researcher Carole LaBonne, PhD, received an H Foundation Bridge Award to continue her work on cells. A number of cancers of great clinical significance are neural crest-derived, including neuroblastomas (among the most common solid tumors of childhood), melanomas, and glioblastomas. The long-term goal of this work is to develop a mechanistic understanding of the development of the neural crest, a stem cell-like progenitor population central to the evolution of the vertebrates, and to understand how diseases such as cancer result from the aberrant regulation of this cell type. Dr. LaBonne’s laboratory seeks to understand at a mechanistic and biochemical level how the stem cell population is formed, what controls the maintenance of its multipotency, how the migratory and invasive behavior of these cells is regulated, and ultimately, how individual neural crest cells are directed to adopt specific derivative fates. Dr. LaBonne’s work resulted in a journal publication and cover page in Science entitled: “Shared regulatory programs suggest retention of blastula-stage potential in neural crest cells.” In addition, Dr. LaBonne will be receiving a highly prestigious R01 grant from National Institutes of Health to further this important work.

Other Support 2014-2015

Patient-Derived Xenografts (PDX) The H Foundation funds provided support for technical personnel for the Patient-Derived Xenograft (PDX) repository. The PDX repository is a joint effort between the Center for Developmental Therapeutics, the Department of Obstetrics and Gynecology, and the Pathology Core Facility, which develops tumor models for a number of different types of cancers. The project involves transplanting pieces of tumors taken from cancer patients and implanting them directly into mice. The resulting tumors retain the characteristics of the patient tumors. These PDX models preserve key features of the specific cancer and better predict clinical outcomes, making them extremely valuable for testing new cancer therapies. H Foundation funds were critical in supporting the PDX repository, whose models have helped identify and assess several new cancer treatments that are being advanced toward the clinic.

The H Foundation Basic Science Symposium The H Foundation funding also was used for the Basic Science Symposium, held at Northwestern on September 17, 2015. The symposium centered on and Cancer and featured speakers from Northwestern, the University of Michigan, the University of Southern California, Cincinnati Children’s Hospital Medical Center, Cornell University, and the University of Virginia. This year’s speaker was Nobel Laureate Roger Kornberg, PhD, of Stanford University School of Medicine. Over 200 guests attended the symposium.

Oncofertility Conference The H Foundation funds also will support the 2015 Oncofertility Conference at Northwestern. This ninth annual conference, hosted by the Oncofertility Consortium, was held on November 3-5, 2015, at Prentice Women’s Hospital. The conference annually brings together more than 150 national leaders in this emerging field and provides information on cutting-edge research in the area of fertility preservation for cancer patients. 5 Educational Enrichment Activities for Basic Science Programs This past year, The H Foundation funds also furthered various programmatic activities including mini-symposia, lectures, and seminars that foster recurring collaborations and interactions among scientists. These collaborative groups enable faculty members in the basic sciences to come together and share their research.

2015 H Foundation Awards and Announcements The following projects were funded in spring/summer of 2015. We are pleased to share highlights detailing each project’s scope and purpose. We look forward to providing additional updates or outcomes in the coming year.

H Foundation Basic Science Synergy Award The H Foundation Basic Science Synergy Grant ($100,000 for year one) was awarded to a team of three investigators for their proposal Integrating Epigenomic and Kinase Signaling in Castrate Resistant Prostate Cancer. Three interrelated projects will explore the idea that castrate-resistant prostate cancer (CRPC) is the result of a complex set of intertwined and interdependent cellular events. CRPC develops when therapies that deplete testosterone, a hormone that binds to and activates the androgen receptor, cease to be effective. Unraveling this network of interconnected molecular events may shed light on how the androgen receptor retains the ability to drive progression of prostate cancer in the absence of testosterone and how effective therapies can be developed for CRPC. The three team members, Debabrata Chakravarti, PhD, professor of obstetrics and gynecology, Sarki Abdulkadir, MD, PhD, professor of urology, and Jindan Yu, MD, PhD, associate professor of medicine, plan to use the data obtained in these studies as the basis of an application to the National Cancer Institute (NCI) for a large, multi- year program project grant on castrate-resistant prostate cancer. Program project grants are prestigious grants that fund multiple projects, which are thematically related and that, when performed in combination, provide enhanced scientific value.

High Throughput Screening and Medicinal Chemistry Pilot Awards Five investigators were awarded H Foundation grants for pilot projects that require the use of the High Throughput Analysis Lab and/or the ChemCore Facility, both of which reside within Northwestern University’s Center for Molecular Innovation and Drug Discovery.

Identifying novel regulators of HIF-1α protein stabilization using a small molecule library screen Navdeep Chandel, PhD, David W. Cugell, MD, Professor of Medicine, will use the High Throughput Analysis Laboratory for this project. The goal of this pilot project is to search for drugs that can block the stabilization of HIF- 1α, a molecule that is maintained at a very low level in cells when there is sufficient oxygen available. When oxygen levels are low, which commonly occurs in rapidly growing tumors with inadequate blood supplies, the stabilization of HIF-1α allows its cellular levels to increase, and this in turn leads to a sequence of events that protects the tumor cells from dying due to insufficient oxygen. Therefore, a drug that can block HIF-1α stabilization could potentially prevent the growth of tumors under conditions of low oxygen.

Identification of novel DYRK1A inhibitors for treatment of pre-B cell and T-cell acute lymphoblastic leukemia John Crispino, PhD, Robert I. Lurie, MD, and Lora S. Lurie Professor of Medicine, will use both the High Throughput Analysis Laboratory and the ChemCore for this project. This new study advances work from a previous investigation that showed a particular kinase (a molecule that phosphorylates other proteins), DYRK1A, is elevated in certain types of lymphoid leukemias. Dr. Crispino’s laboratory tested an inhibitor of DYRK1A, which was produced by a small French biotechnology company and found that it slowed the growth of these types of leukemia cells, using both cell lines and patient samples. However, the company decided to discontinue its efforts to develop this drug for patient use. Therefore, Dr. Crispino proposes to design new DYRK1 inhibitors and then to test their efficacy. 6 Development of an inhibitor specific to the gamma isoform of PI3K, a novel target for cancer treatment PI3K is an enzyme that is known to play an important function in the development of many tumors, and it has therefore been a target for researchers working on cancer therapeutics. The enzyme is composed of two subunits that play different roles in its function. One of these subunits, termed the catalytic subunit, is produced by cells in three different isoforms or flavors. Most intensively studied by cancer researchers have been the α and β isoforms because they are expressed by most types of cells, while little attention has been paid to the γ isoform because it is found in only a minority of cell types. Surprisingly, however, when Tomoko Hayashida, MD, PhD, research associate professor of pediatrics, tested a γ isoform-specific inhibitor on cancer cell lines, he found evidence that this inhibitor had anti-cancer effects. While this suggests that the γ isoform is a promising anti-cancer drug candidate, the inhibitor that Dr. Hayashida tested has too many adverse side effects to be useful clinically. Therefore, Dr. Hayashida proposes to design and test the efficacy of alternative drugs that inhibit the function of the γ isoform of PI3K.

Characterization of a novel small molecule microtubule inhibitor Brian Mitchell, PhD, assistant professor of cell and molecular biology, will use the ChemCore to conduct this pilot study. In contrast to the three projects just described, where the investigators had identified a cancer cell target for which they proposed to develop a drug that could block its action, here Dr. Mitchell has a promising drug but does not know its target. The drug whose target Dr. Mitchell wants to identify seems to act indirectly on microtubules, which are structural elements in cells whose assembly is required for cells to proliferate. While drugs that act directly on microtubules could theoretically have anticancer effects, such drugs affect normal cells as well and are therefore highly toxic. The ChemCore will assist Dr. Mitchell in identifying the target by attaching a label to the drug. When the labeled drug binds to its target or targets inside of cells, the label will allow the targets to be easily identified.

Transforming the future: targeting the ubiquitin system to treat Ewing’s sarcoma In his project, Alexander Statsyuk, PhD, assistant professor of chemistry, will use the High Throughput Analysis Laboratory to screen a library of compounds for drugs that can inhibit a particular component, HECT E3, of a cellular three-step system, ubiquitination, that targets proteins for degradation in the pediatric bone cancer, Ewing’s sarcoma. Intracellular degradation of proteins is a very important process for maintaining optimal levels of proteins, and this process often goes awry in cancer cells. According to Dr. Statsyuk, the ubiquitination system holds enormous potential for anticancer drug development, and to that end, he has already developed a reagent that will facilitate the screening of potential inhibitors of HECT E3. This reagent will be used to develop an investigative procedure that can be used in the High Throughput Analysis Laboratory. Translational Bridge Funding Our newly launched Translational Bridge Program fosters translational collaborations between basic scientists and clinicians to address the most urgent questions in the fields of cancer biology and oncology. Through the Bridge Program, we have an opportunity to accelerate the progress and heighten the impact of translational research by focusing on deep and rigorous basic science concepts.

David Gius, MD, PhD, professor of radiation oncology and pharmacology, and Cesar Santa-Maria, MD, assistant professor of medicine-hematology/ oncology, received funding to support a Postdoctoral Bridge Fellow in their laboratories for one year. Under the co-mentorship of these investigators and a partnering clinician, the fellow will design and execute a translational project targeting breast cancer. The aim of the fellow’s work will be to ultimately propel laboratory work into investigator-initiated clinical trials.

7 Stewardship Report December 2015

Thank You for Your Commitment

Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University are tremendously grateful for The H Foundation’s partnership in funding and accelerating basic science research. You and your community of supporters are advancing collaborative scientists as they work to develop new breakthroughs and treatment options for cancer patients everywhere. We congratulate The H Foundation on 15 years of impactful success and look forward to continuing to build upon our partnership for many years to come. If you would like more information regarding this report or the Lurie Cancer Center, please contact: Elizabeth M. Knollman Associate Director, Major Gifts Development & Alumni Relations Northwestern University Feinberg School of Medicine Arthur J. Rubloff Building, 9th Floor 420 East Superior Street Chicago, Illinois 60611 P. 312-503-1656 F. 312-503-6743 E. [email protected]

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