Scientists with Novel Approaches to Fighting Cancer Awarded $3M

The Damon Runyon Cancer Research Foundation announced that ten scientists with novel approaches to fighting cancer have been named 2018 recipients of the Damon Runyon-Rachleff Innovation Award. Five initial grants of $300,000 over two years were awarded to six early career scientists (four individuals and one collaborative team) whose projects have the potential to significantly impact the prevention, diagnosis and treatment of cancer. Each awardee will have the opportunity for up to two additional years of funding (four years total for $600,000). This year, continued "Stage 2" support was granted to five awardees who demonstrated significant progress on their proposed research during the first two years of the award.

The Damon Runyon-Rachleff Innovation Award funds cancer research by exceptionally creative thinkers with "high-risk/high-reward" ideas who lack sufficient preliminary data to obtain traditional funding. The awardees are selected through a highly competitive and rigorous process by a scientific committee comprised of leading cancer researchers who are innovators themselves. Only those scientists with a clear vision and passion for curing cancer are selected to receive the prestigious award.

This program was established thanks to the generosity of Andy and Debbie Rachleff.

New 2018 Damon Runyon-Rachleff Innovators:

Lawrence A. David, PhD, and Anthony D. Sung, MD
Duke University, Durham

We share our bodies with trillions of microorganisms: the microbiota. The microbiota interacts with our bodies to affect health and disease, including cancer development and response to therapies. For example, in patients receiving hematopoietic stem cell transplantation as treatment for leukemias, lymphomas, and other blood cancers, disruptions in the microbiota have been linked to disease relapse, infections, treatment complications, and survival. Given these serious effects, it is important to understand how to manipulate the microbiota through therapies like prebiotics: carbohydrates that can be ingested to stimulate the growth and maintenance of various bacteria. The challenge is that different people have different microbiotas and therefore may respond differently to the same prebiotic. To address this challenge, Drs. David and Sung have developed a novel microfluidic platform to isolate individual bacteria from a patient's stool sample and grow them against selected prebiotics, allowing an understanding of how a given patient's microbiota may respond to different prebiotics. To do this using conventional techniques would take a stack of petri dishes as tall as the Empire State Building and months of work; their innovative system can do it in a single day. They believe that by using this novel system, they will be able to predict the best prebiotic for a given patient, thereby manipulating their microbiota and improving cancer outcomes. They will test this strategy using patient samples in their artificial gut "bioreactor" as well as in mouse models. The success of this project would lead to clinical trials of personalized prebiotics.

Eric S. Fischer, PhD
Dana-Farber Cancer Institute, Boston

Cancer therapies that target a specific gene product (targeted therapies), for example the oncogenic BCR-ABL by Gleevec, are now a very successful paradigm in cancer treatment. However, many known cancer-driving proteins are recalcitrant to the development of traditional small molecule inhibitors. In recent years, novel pharmacologic strategies have been proposed and developed to tackle this pervasive problem in drug development. One such novel pharmacologic modality is called "degraders," small molecules that hijack the cellular waste disposal system - the ubiquitin proteasome system - to remove a cancer-causing protein from the cell. While the concept has shown incredible success in the case of lenalidomide (Revlimid) for the treatment for multiple myeloma, our understanding of the underlying mechanism is insufficient to broadly apply degraders to cancer treatment. Dr. Fischer's research will expand our molecular understanding for the mechanism of action of degraders, and further develop a novel class of small molecule degraders to target oncogenic gene products. He anticipates that this work will contribute to the development of novel medicines for many cancers.

Arnold S. Han, MD, PhD
Columbia University, New York

Cancer immunotherapy utilizes the body's own sophisticated defenses to kill cancer cells. Recently, strategies that mobilize the immune system to target cancer have shown great promise in the clinic. Despite its enormous promise, however, immunotherapy is only effective in a relatively limited subset of cancers in a limited group of patients. The continued success and advance of cancer immunotherapy will require novel and innovative approaches. T cells are the cells within the immune system that mediate most anti-tumor immune responses. Dr. Han is studying tumor T cells using unique tools to improve our fundamental understanding of tumor immunity and also to directly test a new therapeutic strategy, which is based upon his hypothesis that our bodies produce T cells that are capable of specifically targeting a patient's own tumors. His proposed research investigates a strategy to identify these T cells and enable them to realize their full potential through genetic engineering. His work investigates T cell immunity in human colorectal cancer, a highly prevalent cancer in which immunotherapy has had very limited success. He anticipates his findings will be applicable in other types of cancers as well.

Amaia Lujambio, PhD
Icahn School of Medicine at Mount Sinai, New York

Immunotherapy is revolutionizing the clinical management of a variety of cancers. Unprecedented complete responses have been observed in hepatocellular carcinoma (HCC), a type of liver cancer that shows little response to conventional therapeutic approaches. Unfortunately, the clinical efficacy of nivolumab (Opdivo), a novel immune checkpoint inhibitor, is limited to less than 20% of HCC patients. Understanding the determinants of sensitivity and resistance to nivolumab and developing strategies that overcome resistance are therefore urgently needed to significantly improve the clinical management of HCC patients. Dr. Lujambio will combine the use of a novel mouse model of liver cancer and samples from HCC patients treated with nivolumab to identify genes that are involved in intrinsic and acquired resistance to this therapy. These findings will be critical to define biomarkers to select the HCC patients that are most likely to benefit from this immunotherapy. Moreover, a better understanding of the mechanisms of resistance to nivolumab will help design strategies to overcome resistance, providing novel therapeutic options for resistant patients.

Wayne O. Miles, PhD
Ohio State University, Columbus

Inactivation of the Retinoblastoma 1 (RB) tumor-suppressor gene is a hallmark of cancer. Loss of RB function results in the transcription of genes required for cell growth but surprisingly also cell death. Profiling of RB-deficient cells showed that these cell death mRNAs are induced but not made into protein. Dr. Miles aims to identify the factors that block the production of cell death proteins and determine which of these factors prevent RB-lacking cancer cells from dying. As the RB pathway is disabled in almost all tumors, his research will provide insights into the mechanisms supporting cancer cell survival and as well as those preventing the death of cancer cells.

2018 Stage 2 Damon Runyon-Rachleff Innovators:

Christin E. Burd, PhD
Ohio State University, Columbus

The RAS oncogene is mutated in 20% of all human cancers. Different types of mutations occur that promote cancer initiation and progression, yet we do not yet understand the specificity of how each mutation affects RAS' ability to promote cancer. Unfortunately, despite decades of scientific effort, there are no effective therapies to directly target RAS mutant cancers. Dr. Burd proposes novel, mutation-specific studies of RAS in a variety of tumor types, starting with melanoma, thyroid cancer, and acute myeloid leukemia (AML). The reason why each cancer type appears to "prefer" one RAS mutant over another is unknown; however, she postulates that the subtle differences between mutants are critical for tumor formation. Her research will lead to new understanding of RAS mechanism and function, resulting in better design of novel therapeutics to target RAS for treatment of cancer.

Scott J. Dixon, PhD
Stanford University, Stanford

Dr. Dixon aims to determine whether the altered metabolism of cancer cells creates new vulnerabilities that can exploited therapeutically. "Reductive stress" is a cellular concept in which too much glutathione could lead to cell growth arrest and death. He is investigating how a gene called NRF2 balances the demand for new glutathione synthesis with the need to avoid glutathione-mediated reductive stress. Reductive stress-mediated protein unfolding and aggregation may burden the protein folding and stress response machineries and explain, in part, the heightened sensitivity of cancer cells to inhibitors of these pathways. Thus, his work could also suggest new approaches to selectively eliminate cancers with mutations that lead to high NRF2 expression, using agents that enhance reductive stress. His central goal is to characterize cell-specific metabolic alterations and seek new ways to exploit these differences therapeutically.

Philip A. Romero, PhD
University of Wisconsin, Madison

Dr. Romero is a biomedical engineer whose expertise is in the area of microfluidics. He proposes to develop new technology that can be used to detect circulating tumor cells (CTCs) in the bloodstream. CTCs are cells that have detached from a solid primary tumor and entered into the bloodstream; they can go on to colonize distant sites and form metastases. Detecting CTCs is an enormous challenge, as the cells are present at an ultra-low abundance (one out of billions of blood cells). His approach is to develop a highly specific system, a "DNA-based logic circuit," to detect and profile CTCs, which could ultimately be applied for cancer diagnosis, prognosis indication, and measurement of a patient's response to treatment.

Peter J. Turnbaugh, PhD
University of California, San Francisco

Variations in drug efficacy and toxicity between patients are a major limitation to the long-term treatment of cancer. Even if the initial treatment is successful, cancers can return due to the emergence of cancer drug resistance. Dr. Turnbaugh seeks to determine how the gut microbiome (bacteria residing in the human body) contributes to drug efficacy and resistance. He will combine microbiology and pharmacology approaches to identify new microbiome-based biomarkers for monitoring and predicting acquired drug resistance. The findings will also have broad implications for development of more effective treatment regimens for patients with colorectal as well as other cancers.

Roberto Zoncu, PhD
University of California, Berkeley

Cancer cell metabolism differs from that of healthy cells because cancer cells have extreme requirements for energy. An organelle inside the cell called the lysosome has recently been defined as a "metabolic signaling center," which senses cellular nutrient levels and communicates them to a growth regulator protein called mTORC1. Dr. Zoncu proposes to synthesize novel molecules that can specifically disable the lysosomal-mTORC1 signaling pathway as a new means of starving cancer cells and thus blocking tumor growth. He will investigate how this pathway controls the function of the lysosome and another organelle, the mitochondria, in mediating the resilience of cancer cells to challenges such as starvation, hypoxia and chemotherapeutic drugs. This research may impact all cancer types, but particularly pancreatic and lung cancers, which appear to be uniquely sensitive to levels of mTORC1.

This article has been republished from materials provided by The Damon Runyon Cancer Research Foundation. Note: material may have been edited for length and content. For further information, please contact the cited source.