A Tribute to John Mendelsohn

Published OnlineFirst June 18, 2019; DOI: 10.1158/0008-5472.CAN-19-0989 Cancer Review Research

A Tribute to John Mendelsohn: A Pioneer in Targeted Cancer Therapy Rakesh Kumar1,2,3, Marc Van de Vijver4, Giampaolo Tortora5,6, Fortunato Ciardiello7, Tzipora Goldkorn8, Wilson H. Miller, Jr9, and Larry Norton10

Abstract

Cancer scientists and clinicians are mourning the death of cian, who extended compassion and the gift of his time to one of the most accomplished members of their community: patients, colleagues, and mentees alike. In tribute to Dr. Dr. John Mendelsohn. He was a pioneer in targeted cancer Mendelsohn, Cancer Research has invited his former mentees therapy and was instrumental for the discovery and deploy- and colleagues who were associated with Dr. Mendelsohn for ment of the ﬁrst antagonist epidermal growth factor receptor over three decades to reﬂect on the broad impact of his work. (EGFR) therapeutic antibodies, broadening the concept of Here, we discuss Dr. Mendelsohn's illustrious career at three targeted EGFR therapy to encompass other receptor tyrosine elite academic cancer institutions and hospitals in the United kinases, such as HER2, and developing blocking antibody- States, his acumen to build, grow, and uplift institutions, and combination therapy with chemotherapies or radiotherapy. train a generation of medical oncologists, physician scientists, Dr. Mendelsohn, who died on January 7, 2019, always led by and cancer biologists. His profound legacy on targeted therapy the strength of his accomplishments and the humility of his and cancer research and treatment continue to prolong and character. Above all, he was a well-revered mentor and clini- save the lives of cancer patients globally.

Introduction (EGFR), one of the widely upregulated and hyperactivated receptor-tyrosine kinases (RTK) in human cancer (4–7). His contribu- Targeted cancer therapy is today considered among the most tions served as a guidepost for future scientific efforts to block, effective treatment options for patients with cancer across the downregulate, or redirect the EGFR-coupled mitogenic signaling world (1–3). It provides patients with selective treatment and has by therapeutic antibodies or similar agents (1, 4, 8). Taken been a modern focal point for researchers and clinicians alike. together, Dr. Mendelsphn's collective work cemented the concept Targeted cancer therapy has a very special place in the treatment of targeted EGFR therapy as a model for modifying the functions repertoire of modern medicine; it has extended and saved the lives of other overexpressed RTKs, such as the members of the HER of countless patients with cancer over the past several decades. The family—HER2 and HER3, etc. (9–10). Dr. Mendelsohn's contri- field of targeted cancer therapeutics would be incomplete without butions to targeted cancer therapeutics are just one of many the instrumental contributions of Dr. John Mendelsohn, who examples of his lasting impact to our field. In addition, Dr. passed away earlier this year. Mendelsohn's work in the 1980s Mendelsohn's laboratory served as a springboard for training propelled the conceptual notion of the usefulness of highly many students and fellows, including many of the authors of selective monoclonal antibodies that can act to impair and this article, allowing them to germinate the seeds of their own suppress the functionality of epidermal growth factor receptor scientific programs.

1Cancer Biology Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum, John Mendelsohn: Making Cancer History Kerala, India. 2Department of Human and Molecular Genetics, Virginia Com- John was a pioneer in our ﬁeld, who sought to battle cancer at 3 monwealth University School of Medicine, Richmond, Virginia. Department of both the molecular and clinical levels (11). Dr. Mendelsohn was Medicine, Division of Hematology-Oncology, Rutgers New Jersey Medical closely associated with the mission of "Making Cancer History" School, Newark, New Jersey. 4Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands. 5Medical Oncology, Comprehensive Can- from the earliest stages of his career. He was a native of Cincinnati cer Center, Fondazione Policlinico Universitario Gemelli, IRCCS, Rome, Italy. and graduated from Harvard College in 1958, where he was the 6Medical Oncology, Catholic University of the Sacred Heart, Rome, Italy. ﬁrst undergraduate student in the laboratory of James D. Watson, 7Dipartimento di Medicina di Precisione, Universita degli Studi della Campania the co-discoverer of the structure of DNA. Dr. Mendelsohn went 8 Luigi Vanvitelli, Napoli, Italy. University of California Davis School of Medicine, on to receive his medical degree from Harvard Medical School in Davis, California. 9Department of Medicine, Segal Cancer Center and Jewish 1963. Between 1963 and 1970, he completed his residency and General Hospital, McGill University, Montreal, Quebec, Canada. 10Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. fellowship trainings at Brigham and Women's Hospital in Boston, the NIH and Washington University Medical School in St. Louis, Corresponding Author: Rakesh Kumar, Rajiv Gandhi Centre for Biotechnology, and started his academic career at the University of California San Thycaud Post, Poojappura, Thiruvananthapuram 695014, Kerala, India. Phone: 471-2781-270; E-mail: [email protected] Diego (UCSD) in 1970. Throughout his career, Dr. Mendelsohn had the rare distinction of holding leadership positions and Cancer Res 2019;XX:XX–XX contributing to academics and patient care of three elite academic doi: 10.1158/0008-5472.CAN-19-0989 cancer institutions and hospitals in the United States (Fig. 1). He 2019 American Association for Cancer Research. was the founding director of the UCSD Cancer Center from its

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A B

Figure 1. John Mendelsohn—a visionary leader in cancer research, patient care, and training programs, with key leadership roles at three major Cancer Centers. A, John Mendelsohn at the podium during the groundbreaking ceremony at The University of California San Diego Theodore Gildred Cancer Center C on June 4, 1981. B, John Mendelsohn in his laboratory at The Memorial Sloan-Kettering Cancer Center in New York City. C, John Mendelsohn in his Presidential ofﬁce at the University of Texas M.D. Anderson Cancer Center in Houston. (Credit for photos: A, Courtesy of Special Collections & Archives, University of California San Diego. B, Courtesy of Memorial Sloan-Kettering Cancer Center. C, Courtesy of the University of Texas MD Anderson Cancer Center).

inception in 1977 until 1985 (Fig. 1A), when he moved to Achievement Medal, Distinguished Lifetime Achievement Award Memorial Sloan-Kettering Cancer Center (MSKCC)—when he from the American Society of Clinical Oncology, Margaret Foti was the Chair of Medicine and held the Winthrop Rockefeller Award for Leadership and Extraordinary Achievements in Cancer Chair in Medical Oncology (Fig. 1B). Dr. Mendelsohn moved to Research from the American Association for Cancer Research, Houston in 1996 to become the third President of The University Medal of Honor from the American Cancer Society, and Tang of Texas MD Anderson Cancer Center (MDACC; Fig. 1C), where Prize Medal. Dr. Mendelsohn was an elected member of several he launched new research, patient care, and educational pro- professional organizations, including the National Academy of grams, and created and implemented a roadmap of unprecedent- Medicine. He was also the founding Editor-in-Chief of the journal ed growth, scholarly culture, and public recognition of MD Clinical Cancer Research. For a scientist and clinician who devoted Anderson as the top cancer hospital in the nation for multiple decades of his life to advancing cancer research and revolution- years. In 2011, Dr. Mendelsohn became President Emeritus izing patient treatment, it was a tragic irony not lost on Dr. and head of the newly established Sheikh Khalifa Bin Zayed Al Mendelsohn that he ultimately was afflicted with a life-ending Nahyan Institute for Personalized Cancer Therapy at MD cancer. Anderson. To fully grasp the pioneering influence of Dr. Mendelsohn's For his contributions and leadership in cancer medicine contributions and his effect in shaping targeted therapy today, we and humanity, Dr. Mendelsohn received numerous accolades, begin with reflecting on Dr. Mendelsohn's early work when prizes, medals, distinguished awards, and lifetime achieve- targeted therapeutics was in its infancy and he was preparing to ments awards. These included, among others, Fulbright Lifetime undertake the task of targeting the first growth factor receptor with

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From Blocking EGFR mAbs to HER- and RTK-Directed Therapies

tyrosine kinase activity at a time when only two other tyrosine hematopoietic cancer and the emerging significance of EGFR in kinases were known, PDGFR (12) and c-Src (13). We highlight supporting tumor cell growth, Dr. Mendelsohn forged a landmark how Dr. Mendelsohn's work validated the concept of targeting collaboration in 1980 with another UCSD faculty member, Dr. hyperactivated RTK in cancer cells by monoclonal antibodies or Gordon Sato, who had identified the role of specific growth factors other target-directed agents. and hormones in sustaining the growth of normal and tumor cell lines in culture without animal serum (28). Dr. Sato's work EGFR's emerging significance in human cancer and provided the much needed serum-free tissue culture system to Mendelsohn's early interest in the 1980s examine the effect of specific growth factors in cultured cells, and ThestoryofEGFRinhealthanddiseasesistracedtotheearly his work prompted other scientists to search for secreted paracrine 1960s when Stanley Cohen's team discovered a growth stim- or autocrine growth factors. Dr. Mendelsohn also utilized such a ulatory ligand (14), the epidermal growth factor, and subse- serum- and albumin-free system to study the growth rate of quently, its target receptor EGFR, and demonstrated its role in normal human lymphocytes (29). stimulating the growth of epidermal cells (15). One of the most Dr. Mendelsohn's hypothesis of blocking anti-EGFR monoclo- exciting phases of cancer biology in the early 1980s was the nal antibodies also evolved from the work of a Salk Institute realization that a number of transforming viruses encode colleague, Dr. Ian Trowbridge, who demonstrated the ability of a oncogenic cell surface proteins with tyrosine kinase activity monoclonal antibody against the transferrin receptor (TfR) to with an ability to support the growth of target cells (16). This inhibit the growth of cancer cell lines in culture models or in mice was followed by heightening the role of EGFR and the second xenograft models (30, 31). Dr. Mendelsohn and Dr. Trowbridge member of the family member HER2 in growth regulation of established that anti-TfR monoclonal antibodies block the growth cancer cells (17, 18), and then, cloning of the human EGFR of stimulated, cycling, but not quiescent, lymphocytes by selec- and HER2/c-neu in 1984 and 1986, respectively (19, 20). tively binding to TfR (32). This provided additional evidence Together, these events formed the basis of the hypothesis that that a blocking anti-receptor mAb could, in principle, be used to human EGFR and HER2 growth factor receptors might be interrupt the growth of cycling cells. upregulated in human cancer. There was a general thrust in Drs. Mendelsohn and Sato's team explored the possibility of the fieldtofullyunderstandthecellular events that underline blocking the growth of tumor cells by interfering with the binding the cancerous functions of EGFR and HER2. This led to evi- of growth-promoting polypeptide factors and provided the first dence of increased EGFR expression in a variety of tumor cell evidence that anti-EGFR mAb could effectively be used to inhibit lines and growth stimulation by EGF (21) as well as the first the growth of cancer cells in culture and in animal xenograft demonstration of EGFR protein upregulation in human lung models (33–35). Dr. Tomoyuki Kawamoto, a postdoctoral squamous cell carcinomas (22) and HER2 protein in breast research fellow in Dr. Gordon Sato's lab, developed mouse tumors (23, 24). All of these early observations helped solidify hybridomas secreting highly specific anti-EGFR mAbs, including the notion that overexpression of EGFR and HER2 and asso- 225 IgG, with the ability to almost fully compete with high ciated mitogenic signaling drive the process of an uncontrolled affinity, with the binding of radiolabeled EGF, block ligand- growth of cancer cells. induced EGFR phosphorylation (implying, resulting signaling), The seeds of Dr. Mendelsohn's seminal contribution to the and growth stimulation of cultured cells (36–38). Colleagues who concept of using highly specific blocking anti-EGFR monoclonal worked closely with Dr. Mendelsohn at UCSD include Dr. Hideo antibodies as anticancer agents (Fig. 2A) can be traced back to his Masui who later relocated to MSKCC with Dr. Mendelsohn in earlier general interest in understanding the role of growth factors 1985 and Dr. Gordon Gill and Dr. Denny Sato. Remarkably, this in hematopoietic malignancies, that is, his effort to define the was the first example of the use of anti-EGFR mAb as a therapeutic role of T-cell growth factor or prostaglandin E1 in the regulation agent to inhibit the growth of tumor cells with high EGFR and the of lymphocytes or granulocyte/macrophage progenitor prolife- start of an era of blocking/antagonist antibodies against EGFR ration from patients with chronic lymphocytic leukemia (CML; family members (Fig. 2A and B). It is noteworthy that the notion refs. 25, 26). During this time, he also delineated the contri- of agonist anti-EGFR mAb prevailed at that time (39, 40). bution of serum growth factors in supporting the growth of lymphocytes (27). These early representative studies at UCSD, Blocking therapeutic EGFR monoclonal antibodies from bench combined with the fact that Dr. Mendelsohn founded the to bedside UCSD Cancer Center, initially named "Theodore Gildred Cancer After relocating to Memorial Sloan-Kettering Cancer Center Center," redirected his core interest to solid tumors, which was in 1985, Dr. Mendelsohn continued with his quest to translate just beginning to surface back then. Encouraging leads, solid the EGFR blockage hypothesis to the bedside. Studies were scientific reasoning, and a spectrum of UCSD and Salk Institute focused on defining the fate of receptor-bound EGFR mAb and colleagues he was about to start collaborating with back then the mechanism of the growth inhibitory action of blocking further strengthened Dr. Mendelsohn's vision for continuing his anti-EGFR mAbs, and the development of appropriate preclin- quest to discover the role of EGFR in human cancer, to translate ical model systems to fully understand the biology of EGFR his studies from bench to bedside while at MSKCC, and to blocking antibodies mAb biology to advance these molecules continue to develop C225 as an anticancer drug at MDACC. for cancer treatment. By 1989, Dr. Mendelsohn had sufficient experimental data to start the first phase I clinical trial of radio- Mendelsohn's scientific quest: forging collaboration with labeled 225 mAb, which was also the first clinical trial of colleagues targeting a growth factor receptor (41). These early formative years prepared Dr. Mendelsohn for the In parallel, Dr. Mendelsohn continued to gain deeper mech- subsequent major findings in targeted therapy in the next phase of anistic insights of various cellular and biochemical aspects of his career. Primed by his interest in growth factor research in 225 mAb action in tumor cells (42–46). Because the presence of

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A 225 mAb Growth factors EGFR

Growth signals Host cell Tumor cell Autocrine growth stimulation Paracrine growth stimulation

B Ab 225 4D5 Ab Ab RTK EGFR HER3 HER2 HER4 PPTKI PP Modulation of Homo- and Heterodimerization Receptor internalization, T Half-life, and Redistribution Signaling cascades-routers Integration-bifurcation Cytoskeleton Cellular responses Survival remodelling Gene expression Proliferation Apoptosis Invasion-Metastasis Cell cycle progression DNA repair Modulation of chemo- and radiosensitivity

Extracellular FDA approval-C225 autocrine loop C mAb4D5 combination therapy EGFR EGFR-phos inhibition Chimeric FDA with chemotherapies Interest in EGFR antagonist 225 mAb HER2-phos C225Ab C225 and radiotherapy growth factors hypothesis 225 mAb clinical trials 1962 1973 1979 1980 1981 1983 1984 1986 1989 1991 1992 1994 1998 2000 2004 2010 2011 ? EGF EGFR Viruses & EGFR in EGFR HER2 mAb4D5 Humanized FDA Iressa HER3 Stable growth factor cancer cells cloning cloning growth mAb4D5 herceptin EGFR-TKI mAb reversal- receptors proliferation inhibition herceptin acquired resistance?

Figure 2. EGFR blocking antibody hypothesis and HER growth factors in cancer research. A, Cartoon illustrating the binding of autocrine and paracrine growth factors that are TGFa, heregulins, etc., to the cell surface EGFR or other surface RTK and, in turn, the resulting signaling and functions. These ligand-induced events could be blocked by highly selective anti-EGFR antibodies as hypothesized by Dr. Mendelsohn. B, Activation of HER family members by ligand-induced homo- and heterodimerization and its modulation by blocking antibodies. Examples of receptor-centered and post-receptor processes inhibited (red ﬁrst letter in boxes), induced (green ﬁrst letter in boxes), or modulated either ways by blocking antibodies. C, Timeline of representative, but not all, major advances in growth factor research in the context of Dr. Mendelsohn's interest in growth factors and work discussed here. Events in blue, Dr. Mendelsohn's research interests and contributions. The timeline of events is not drawn to scale.

the EGFR and its ligand in the same cancer cell alone does not excellent tool to study the biochemistry and subcellular re- establish a functional autocrine loop in tumor cells (47), Van distribution of EGFR. For example, Goldkorn and Mendelsohn de Vijver, Kumar, and Mendelsohn provided the experimental demonstrated that EGFR phosphorylation could also be inﬂu- evidence to prove this concept and to establish that anti-EGFR enced by a growth inhibitory factor such as TGFb (50). Simi- mAbs function by interrupting an extracellular autocrine loop larly, as dysfunctional growth regulation of cancer cells is (48) as opposed to an intracellular autocrine loop observed in driven by co-hyperactivation of cAMP-dependent protein kinase the case of PDGFR and its ligand, which are also co-overexpressed type I (PKAI), Tortora and Ciardiello provided evidence of a in tumor cells (49). These EGFR antibodies served as an superior growth inhibition of murine xenografts by combining

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blocking EGFR antibodies with PKA inhibitors (51). In addition, of the recombinant humanized mAb 4D5 (rhuMAb HER2) in EGFR pathway also interacts with Toll-like receptor 9 (TLR9) as HER2-overexpressing patients with metastatic breast can- TLR9 agonists restore sensitivity in cetuximab-resistant xenografts, cer (64). Following the success of preclinical modeling of the probably by boosting the antibody-dependent cellular cytotoxic- combination therapy involving 225 mAb with doxorubicin or ity (ADCC) activity of cetuximab (52). In addition to these and paclitaxel, Dr. Mendelsohn along with Dr. Baselga and Dr. many other molecular studies, Dr. Mendelsohn's laboratory Norton provided preclinical xenograft models showing a super- actively pursued the possibility of EGFR antibody-based combi- ior efficacy of combining Herceptin with chemotherapies (65). nation therapies with commonly used chemotherapies (53–55). This established the concept of combining antireceptor anti- In one such study, Miller and Dr. Mendelsohn along with the lead bodies with paclitaxel or doxorubicin. These studies paralleled author Dr. Jose Baselga (also a fellow in Dr. Mendelsohn's the concept and feasibility of using a blocking EGFR antibody laboratory) and other team members established the effectiveness targeting an upregulated growth factor receptor in human of combining EGFR blocking antibodies with doxorubicin as cancer that was firmly established by Drs. Mendelsohn and compared with individual agents (56). The 225 mAb was later Sato's team in 1984. humanized to avoid an immune response against the murine Like most of other forms of targeted therapy, EGFR antibody antibody and developed as a chimeric human:murine antibody therapy and tyrosine kinase inhibitors (TKI) therapy need to C225, eventually labeled as cetuximab or Erbitux. All these overcome two limitations for maximizing its effectiveness. These advances led to the FDA approval of C225 in 2004 for patients include the nature of cellular determinants of drug sensitivity and with advanced colorectal cancer in combination with irinote- the invariable problem of acquired resistance to therapy. In can (57) and for treating advanced squamous cell carcinoma of general, the development of therapeutic resistance associated with head and neck (SCCHN) along with radiotherapy in 2006 (58), differential expression and activities of signaling pathways, dif- and for relapsed aggressive SCCHN as a combination therapy with ferential convergence and bifurcation of signals through router platinum in 2011 (59). In brief, as a physician-scientist, Dr. proteins or protein complexes, and differential gene expression— Mendelsohn brought a unique combination of scientific curiosity, all feeding into well-orchestrated cellular programs leading to the drive, lead science teams, patience, and humanity needed to carry cell survival and/or growth in addition to other hallmarks of out exhaustive research and clinical trials. cancer. One such generally obligatory growth factor pathway is HER3 (8–10), the third member of the HER family whose upre- The hypothesis of targeted EGFR therapy as a general concept gulation correlates well with poor prognosis of a variety of cancer Dr. Mendelsohn was a visionary scientist, as he recognized the types (Fig. 2B). HER3 is unique as it lacks hyperactivated kinase value of lessons and applications from his EGFR work to other activity but contributes to cancer signaling by virtue of its ability to RTKs such as HER2, an oncogene upregulated in breast and other form heterodimers with HER2 or EGFR—the former being the human tumors. At that time, the same rationale was adopted by preferred HER3 partner. Following the lessons from blocking academic and pharmaceutical research laboratories, which gen- EGFR antibodies, a promising approach to overcome the acquired erated anti-HER2 monoclonal antibodies directed against the resistance to EGFR-directed therapies as well as for treating HER3 extracellular HER2 domain and demonstrated growth inhibitory overexpressing tumors, includes use of anti-HER3-antibodies as activity of HER2 mAbs in tumor cells with high HER2 expres- well as bivalent antibodies cotargeting HER3 and HER2 or EGFR sion (60, 61), including the growth inhibitory anti-HER2 to inhibit its activation by ligands and, in turn, suppress its mAb4D5 developed by Genentech in 1989 (61). As the mecha- dimerization with HER2 or EGFR (Fig. 2B). Such antibodies are nism of such monoclonal antibodies was not fully clear at the at different stages of clinical development and have shown clinical time, Dr. Mendelsohn's laboratory wished to expand the concept efficacy (Fig. 2C; refs. 66–71). In addition to HER-directed anti- of using blocking RTK antibodies beyond EGFR, and hence, the bodies, Dr. Mendelsohn's work also catalyzed the development of laboratory set-up collaboration with Genentech to obtain anti- other modalities to target HERs, including TKIs such as Iressa and HER2 mAb4D5. In this context, Kumar and Mendelsohn along subsequent generations of TKIs with distinct model of with Shepard from Genentech went on to demonstrate in 1991 actions (72). The concept of blocking therapeutic antibodies has that anti-HER2 mAb4D5 indeed blocked HER2 phosphorylation also been applied to other upregulated RTKs, such as MET and and prevented its downregulation in a manner that was indepen- IGF1R receptors, which have been shown to confer therapeutic dent of activation of EGFR by its ligand (62). This was the first resistance and are also excellent targets for combination EGFR report showing the ability of anti-HER2 mAb 4D5 to inhibit HER2 therapies (73–77). Further, therapeutic resistance to HERs anti- phosphorylation on tyrosine residues. These findings offered bodies or TKI might involve nonreceptor kinases such as SRC (78) clues about the usefulness of anti-HER2 mAb 4D5 to inhibit the as well as other pathways in a cell-type context-dependent man- pathways dependent on HER2 phosphorylation, contributing to ner. In addition to the potential involvement of HER3, among understanding the mechanism of growth inhibitory activity of other mechanisms that are not discussed here, these include mAb 4D5. During this time, anti-HER2 mAb 4D5 was humanized inherent or acquired mutations in HERs or signaling components. in 1992 by Genentech by an in-frame insertion of mAb 4D5's This is an area of active research, which has not yet taken full complementary determining regions into a human immunoglob- advantage of postgenomic datasets to start obtaining a compre- ulin consensus sequence (63) and was developed as rhuMAb hensive portrait of therapeutic resistance in physiologic setting by HER2 or trastuzumab, or Herceptin for the treatment of the focusing on a battery of molecules/pathways rather than a single subgroup of breast cancer patients with HER2 gene amplification molecule—unless the cell is addicted to such a molecule(s). The and overexpression. authors believe that the goal of a stable reversal of therapeutic To further aid the clinical development of Herceptin, Dr. Jose resistance against RTK-directed therapies might be benefitted by Baselga worked with his mentors, Dr. Mendelsohn and Dr. revisiting some of these or new testable hypotheses that are being Larry Norton and colleagues, and demonstrated clinical activity formulated (Fig. 2C).

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John Mendelsohn: A Caring Mentor and happy to advise us on the key rules to build a modern cancer center Colleague conjugating science with hospitality and humanitarianism. His teachings have imprinted our lives and mission as oncologists. Over a period of nearly 5 decades of his illustrious scientific career, Dr. Mendelsohn's interactions with his mentees have Tzipora Goldkorn. In 1987, I had the honor of joining John inspired a large number of his colleagues to meaningfully con- Mendelsohn at MSKCC. For me, it was a major move from tribute to cancer research and treatment. We learned from Dr. mathematically driven physical chemistry and protein biochem- Mendelsohn how to spot an obscure scientific question of par- istry into the overwhelming complexity and heterogeneity of amount importance, persist with our scientific creativity, and keep cancer research. I could not have been luckier than having the an eye out for equally important incremental contributions that support and vision of a leader in the field. Dr. Mendelsohn guided can lead to major advances over time. Provided below are per- my transition into this field, inspiring to join his heroic battle to sonal recollections from us and from two UCSD guest colleagues "make cancer history." In facing these challenges, Dr. Mendelsohn of Dr. Mendelsohn, Dr. Denry Sato (Manzanar Project Founda- was always cheerful, energetic, and optimistic. He was a true role tion, Wenham, MA) and Dr. Gordon Gill (Emeritus Professor, model with genuine and endless commitment to junior faculty. UCSD, La Jolla CA), who were involved in the original discovery. Furthermore, Dr. Mendelsohn was always curious and welcomed new ideas. He encouraged my interests in exploring how different Rakesh Kumar. I had the privilege of being part of Dr. Mendel- growth factors, such as TGFb, could affect the biology of sohn's Receptor Biology laboratory as a mentee and faculty, and EGFR (50). In addition, he supported the ideas of connecting of being his collaborator and colleague for over 30 years. My sphingolipids to EGFR biology (85). His unique mentorship first meeting with Dr. Mendelsohn in June 1988 was a turning assisted immensely in formulating my own research program for point in my research career, as he helped me evolve a frame- years to come. Following Dr. Mendelsohn's legendary example work for my research program focused on the scientificques- and philosophy, I have devoted my own career to training the next tions of utmost importance of our time. His contributions and generation of lung biologists. This is what I consider to be John mentorship underscored the power of persistence in revealing Mendelsohn's greatest inherited effect (86, 87). scientific mysteries, and allowed us to unearth new facets of the HERs, heregulin action, and resulting signaling pathways and Wilson Miller. I had the opportunity to be mentored by router p21-activated kinases to cellular functions and gene Dr. Mendelsohn during the transition from my postdoctoral expression machinery via cytoskeleton and chromatin remo- work with Dr. Ethan Dmitrovsky and my independent laboratory, deling in cancer cells (79–81). Dr. Mendelsohn was always as well as much later in my career when we collaborated intellectually curious and dedicated to his profession, and as members of the Worldwide Innovative Network (WIN) would routinely immerse himself into our late evening scien- Consortium, of which John was the founding chairman. I always tific discussions and continued to closely follow and interact considered Dr. Mendelsohn as a model for the translational can- with me on the topics in the years to come until late 2018. I cer research to which I have dedicated my career. It has been a have had the good fortune of having countless such interactions particular pleasure to renew our collaboration within the WIN with Dr. Mendelsohn and have the utmost respect for his Consortium, and this work continues to expand Dr. Mendelsohn's ingenuity, humility, and his accomplishments as one of the contribution to targeted therapy as described in a recent collab- greatest cancer physician-scientists of our time. orative work with him (88).

Marc Van de Vijver. As an extension of my work as a graduate Larry Norton. My memories of John certainly include appreciation student at the Netherlands Cancer Institute (Amsterdam, for his erudition regarding growth factor biology and the thera- the Netherlands), I spent time in Dr. Mendelsohn's Receptor peutic disruption thereof. These ideas have changed clinical Biology laboratory in 1989. Having worked on HER2 gene practice in so many ways that his legacy as a scientific thinker is amplification in breast cancer in the Netherlands Cancer Insti- vast. But what might be less apparent is how he converted those tute and interested in the therapeutic potential of HER2 tar- ideas into clinical trials leading to practical implementation. He geted therapy (23, 82), Dr. Mendelsohn's lab was at that time did this by—to use the simplest and yet most powerful term— the best place to turn. The stimulating scientific atmosphere in leadership. John had the talent to always look for the best person Dr. Mendelsohn's laboratory and the interactions between the in the room to answer a question as opposed to feeling the need to laboratory and clinic at Memorial Sloan Kettering Cancer prove to everyone that he was the smartest person in the room. If Center have had a positive and lasting impact on my research the conversation was leaning in the direction he favored, he had and clinical work after that. I have fond memories of the no compulsion to claim ownership of that opinion; he was very scientific and social interactions with Dr. Mendelsohn then comfortable with letting others claim credit. As a result, he and in the years thereafter. brought out the best in everyone and we made progress most rapidly, as a collective effort. By his example, he taught me the Giampaolo Tortora and Fortunato Ciardiello. Dr. Mendelsohn value of eschewing internal competition. Because of our interest has been to us the extraordinary synthesis of a true gentleman in breast cancer and our knowledge of the work of Bill McGuire and an open-minded pioneer scientist. He fostered our curiosity and then Dennis Slamon in identifying HER2 as a promising to explore new areas for the EGFR role and interactions, and therapeutic target, it was easy for John to recruit the involvement Dr. Mendelsohn was always enthusiastic when we described new of Jose Baselga and me into the nascent field of anti-HER2 anti- players in the EGFR signaling network and the possibilities to body therapy. He ran laboratory meetings with brilliance and interfere with such molecules in a cooperative fashion with EGFR benevolence, settled interpersonal disputes with wit and his inhibitors (83, 84). Along with his scientific mentoring, he was serene aura, supported clinical translation with enthusiasm, and

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made us all feel an integral part of noble mission—in one word, your vision and ignore skeptics. Second, John sought community leadership. support, something little done in our young school of medicine. These same skills enabled John to successfully lead the Depart- He succeeded in establishing a cancer research center in a small ment of Medicine at Memorial Sloan Kettering through a period of building adjacent to the downtown hospital; he also established a expansion and re-organization, a trend that continues to this day. cancer service that functioned within the existing hospital system. His self-confidence translated into modesty. Indeed, he worked John Mendelsohn was the founder of what has now become the beside me in the clinic and never asserted his hierarchical supe- highly successful John and Rebecca Moors NIH-supported Com- riority. In addition to his laboratory and administrative expertise, prehensive Cancer Center. There are some recognizable traits that he was a superb clinician, caring as well as knowledgeable. made John successful at UCSD, Memorial Sloan Kettering, and Working together with Vincent DeVita, the then Physician-in- MD Anderson. He recognized and used new methodologies to Chief, John established divisions of hematologic oncology, solid- develop cancer therapeutics; he was a builder with a vision; he was tumor oncology, and general medicine, with identified leaders a leader whose style was to encompass and bypass opposition melded by John into a coordinated program. His legacy in this rather than be diverted by it; he brought the community into the regard is also exemplary. When he left MSKCC to move to take academic world with a shared common enemy: cancer. MDACC's leadership, he left a smooth functioning department well-suited for growth not only in terms of skillful, compassionate care but also dedicated to the integration of correlative science and Concluding Remarks scientifically-directed clinical research initiatives. Dr. John Mendelsohn's contributions in the development and shaping of the field of targeted and personalized cancer medicine Guest colleague Denry Sato. I recall that when Gordon moved to therapy combined with the impact of his lifetime work on become the director of the Alton Jones Cell Science Center in Lake improving the lives of patients with cancer will always be cher- Placid, New York, in 1983, Hideo joined John's lab and later ished by his colleagues and the cancer research community. He moved with John to Sloan-Kettering. Although John and Gor- was a true pioneer in targeted therapy that always imbued his don's collaboration was relatively short, it was a very productive work with the spirit of team science. Dr. Mendelsohn's work on 2 years. Our collaborative research provided the proof of principle therapeutic EGFR blocking antibodies either alone or in combi- that monoclonal antibodies that blocked normal growth factor nation with chemotherapies or radiotherapy has already impact- receptor function could be used as therapeutic anticancer agents. I ed cancer patient care in significant ways. In addition, his work has also believe that we jumpstarted the idea of the effectiveness of also positively impacted the development of antibody-based using intracellular signaling pathways as targets for therapeutic effective therapeutics against other HER family members and cell agents. surface RTK, at-large, and catalyzed the development of additional strategies to impair the HERs kinase activity. Our training, learn- Guest colleague Gordon Gill. John Mendelsohn and my labora- ing, and professional interactions with Dr. Mendelsohn over the tories were adjacent on the 5th floor of the Basic Sciences Building. years were meaningful. He has left a deep impact on our scientific We were friends but not research collaborators. That happily philosophy, impacted our career trajectories, helped us stay changed when John, working with Tomoyuki Kawamoto, a Jap- engaged in science, and passed his values to our trainees. He will anese postdoctoral fellow in Gordon Sato's lab, produced a series be missed by all, but he will continue to live on through his work of monoclonal antibodies directed to EGFR. Since we were for a long time to come. studying EGFR and growth control, collaboration was natural. Together we characterized a subset of these monoclonal antibo- Disclosure of Potential Conflicts of Interest dies as antagonists of EGF binding, regulators of EGF biological G. Tortora reports receiving a commercial research grant from and serves on responses proportional to EGFR concentration and inhibitors of the advisory boards of Merck, Celgene, Novartis, Incyte. No potential conflicts of EGF-stimulated growth of cells in culture and tumor growth in interest were disclosed by the other authors. nude mice as discussed above. In subsequent years, John worked to develop one of these monoclonal antibodies as therapeutics for Acknowledgments human cancer. My lab used them to immune-affinity purify EGFR, The authors thank Dr. Gordon Gill for his critical reading and editing the clone the gene, and characterize structure:function relationships. manuscript, and thoughts on Dr. Mendelsohn. The lead author apologizes to additional Dr. Mendelsohn's trainees and colleagues who could not be reached At UCSD, John led an initiative to establish a cancer center. He fi in a timely manner for including their thoughts in this article, and thanks rst worked to recruit faculty whose research could link in some Aswathy Mary Paul for her help with cartoons and references. way to cancer biology. There was skepticism from some senior faculty. John did not oppose these but worked with supporters. I Received March 25, 2019; revised May 1, 2019; accepted May 28, 2019; admired this style of leadership: build with those who support published first June 18, 2019.

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From Blocking EGFR mAbs to HER- and RTK-Directed Therapies

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A Tribute to John Mendelsohn: A Pioneer in Targeted Cancer Therapy

Rakesh Kumar, Marc Van de Vijver, Giampaolo Tortora, et al.

Cancer Res Published OnlineFirst June 18, 2019.

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