The 8th annual Scholar re-treat featured presentations by Scholars and Mentors in each of the topics of the four most recent annual forums: the Biology and Treatment of Primary Brain Tumors, immunotherapy and Breaking Tolerance, Cancer genomics, and Epigenetics. One extremely heartening theme that was common to all of these sessions was that it was clear that our ability to study human tumors directly has increased vastly. no longer is it necessary to study only models and cells that are remote approximations of patients’ own tumors. now the trip between patient tumor, hypothesis generation and testing in the laboratory, and back to the patient is occurring nearly continuously, a vast improvement in recent years.

This retreat was fortunate to benefit from the experience of Forbeck stalwart Chuck Sherr (St. Jude’s, Memphis) who kicked off the retreat with a fascinating discussion of why if one particular type of mutation is selected in a cancer cell, another is not, and how this can teach you about the cancer’s cell of origin. The Brain Tumor session that followed, chaired by Martine Roussel (St. Jude’s, Memphis), was characterized by the type of bedside-to-bench investigation that is providing information so much more rapidly today, even in the challenging disease of glioma.

The meeting began with a talk by the keynote speaker, David Cheresh, Ph.D., Vice Chairman of Pathology, University of California, San Diego that described his fascinating journey from studies of antibodies to the discovery that defined the role of integrin in angiogenesis, including a detour through a landmark Supreme Court case. In the early 1990’s, David had made the seminal discovery that angiogenesis could be inhibited by blocking surface receptor on endothelial cells. He tested RGD peptides supplied by Merck for their anti-angiogenic effects in tumor models. Integra, a company that co-owned five patients (with the Burnham Institute) to variants of RGD peptides, sued Merck for infringement of patent rights. The suit was ultimately reviewed by the Supreme Court. The Court decided in favor of Merck/Cheresh and held that “the use of patented compounds in preclinical studies is protected...as long as there is a reasonable basis for believing that the experiment will produce ‘the type of information that are relevant to an IND and NDA.'” Cheresh gave a mesmerizing first-person account of the scientific and personal context of this important Supreme Court case that continues to shape investigational use of patented reagents in research. As a life lesson, he emphasized the need to doggedly pursue those studies that are of personal importance, irrespective of the obstacles.

The scientific session on Friday morning focused on Cancer Genomics. Dereck Chiang, Ph.D. (Novartis) discussed the challenges that he faces daily in terms of the clinical translation of the ever-expanding cancer genomic landscape and the need for thoughtful clinical trial design. Sharon Diskin, Ph.D. (Children’s Hospital of Philadelphia) unveiled novel single nucleotide polymorphism that may underlie unique clinical features of neuroblastoma subtypes. Chris Putnam, Ph.D. (University of California, San Diego) provided an overview of how model organisms, such as the baker’s yeast Saccharomyces cerevisiae, can be used to dissect complex genetic interactions on a “systems” level. Bob S. Carter, MD, PhD, an invited mentor and Chairman of Neurosurgery at the University of California, San Diego, shared an extraordinary career that spans the discovery of clinical importance of Ras in prostate cancer, the construction of chimeric T-cells as a tool for molecularly targeting oncogenes, and the discovery of exosomes as a clinical diagnostic and therapeutic platform. For career guidance, Carter emphasized the importance of collaborative endeavors and innovation through inter-disciplinary investigations.

The session on Friday afternoon focused on Epigenetics. Grant Challen, Ph.D. (Washington University School of Medicine) spoke on the importance of DNA methyltransferases and DNA methylation in hematopoietic stem cell fate decision. Gary Chung Hun, Ph.D. (University of California San Diego) described his work elucidating the molecular physiology associated with aberrant Epidermal Growth Factor Receptor (EGFR) signaling. Chris Vakoc, Ph.D. (Cold Spring Harbor Laboratory) discussed the role of the BET bromodomain protein BRD4, as a drug target in acute myeloid leukemia. Anindya Dutta, MD, PhD, an invited mentor and Chairman of Biochemistry and Molecular Genetics, University of Virginia, shared with the Scholars an intellectual odyssey through molecular mechanisms that govern DNA replication and then on-coding RNAs critical for regulating these mechanisms. Dutta’s advice to young investigators is that “it is always worthwhile to take the ‘high road’ when you are placed in an unfortunate situation. The individuals that you lash out against today will inevitably become your Reviewers in the near future.”

The Saturday morning session focused on Tumor Metabolism. Julie-Aurore Losman, M.D., Ph.D. (Dana Farber Cancer Institute) showed work suggesting that the EGLN1 complex, a critical oxygen sensor for cellular metabolism, may harbor functions outside of its canonical role. Kathryn Wellen, Ph.D. (University of Pennsylvania) provided data suggesting that metabolic disturbances can translate into genomic instability and altered DNA damage repair. Michael Cox, Ph.D., an invited mentor and a tenured Professor at the University of Wisconsin, described his pioneering work uncovering mutations that mediate evolution of extreme resistance to ionizing radiation and the pertinence of these mutations to therapeutic development for cancer patients. Importantly, many of these mutations modulate processes independent of DNA damage repair. For the Scholars, Cox emphasized the importance of cultivating and training the next generation of scientific investigators.

The final session of the meeting focused on Resistance Mechanisms. Mari-Francis Arteaga, Ph.D. (Universitatsklinikum Munster, Germany) described the importance of PHF8, a lysine demethylase, as a molecular sensor for mediating retinoic acid treatment response in acute promyelocytic leukemia (APL). Cory Johannessen, Ph.D. (Dana Farber Cancer Institute) rereviewed his work demonstrating molecular pathways responsible for acquired therapeutic resistance to molecularly targeted agents. Kristopher Sarosiek, Ph.D. (Dana Farber Cancer Institute), discussed assessment of apoptotic potential in various organs to better understand developmental programming. I spoke in this last session describing miRNA degradation as a novel mechanism of acquired resistance to chemotherapy. The degradation of key miRNAs results in simultaneous de-repression of multiple DNA repair process. Moreover, such resistance can be circumvented by retroviral gene therapy.