Icahn School of Medicine at Mount Sinai
With the advent of whole-genome sequencing, much of the current research effort focuses on devising so-called ‘personalized’ therapies targeted to specific tumor mutations in individual patients. And for good reason—I continue to write grants, design projects and publish research on the topic!
Yet the overwhelming complexity of the disease, which involves an ever-growing number of ‘driver’ mutations, has me pause for a bit and reconsider. What are the key obstacles facing oncologists today? How can we help, today? Can we devise ‘non-personalized’ therapies beneficial to the greater number?
Resistance to radiation therapy is relevant to one in two cancer patients. The debilitating side effects of chemotherapeutic agents used to amplify the effects of radiation is another major issue. We have developed a whole-organism model of resistance to radiation therapy in zebrafish, which allows us to screen for drugs that suppress the therapeutic block but have otherwise no effect on animal development or physiology. We recently nailed several drugs that accomplish the desired effect. With the Prize’s generous funds, we will determine whether these compounds are viable candidates for use in humans.
Samuel Sidi is an Assistant Professor of Medicine, Developmental and Regenerative Biology, and Oncological Sciences at the Icahn School of Medicine at Mount Sinai. Originally from Paris, France, he graduated with a B.Sc./M.S. in Genetics from Paris VII University. He then completed his graduate studies at the Max-Planck Institute in Tubingen, Germany and the Ecole Normale Superieure/Paris VI University, graduating in 2004. His Ph.D. thesis focused on a large-scale screen for mutations affecting auditory hair-cell transduction in zebrafish, which led to the discovery of ion channels essential for the sense of hearing. Dr. Sidi conducted his postdoctoral studies with A. Thomas Look at the Dana-Farber Cancer Institute at Harvard Medical School, where he developed a zebrafish screening platform for drug and target discovery in radioresistant cancer. Dr. Sidi’s current research focuses on the very first hits from a small-molecule screen that identified chemical suppressors of radiation resistance driven by mutant p53. Several of these compounds restore tumor cell sensitivity to radiation therapy in head-and-neck cancer models, defining first potential treatment strategies for an otherwise invariably fatal disease. Dr. Sidi’s prior honors and awards include PhD scholarships from the Max-Planck Gesellshaft, Association pour la Recherche sur le Cancer (ARC) and Fondation pour la Recherche Medicale (FRM), and cancer research grants and awards from the NIH/NCI, the Claudia Adams Barr Foundation and JJR Foundation, and a young-investigator award from the prestigious Searle Scholars Program.
Anticancer Drug/Target Discovery in Zebrafish
Radiation therapy (RT) targets DNA to trigger tumor cell death, and is a standard of care in head and neck squamous cell carcinoma (HNSCC) and many other cancers. Unfortunately, tumors often acquire genetic mutations that allow them to evade cell suicide in response to DNA damage, leading to resistance to RT (R-RT) and treatment failure. No drugs are available that restore sensitivity to RT in patients, and HNSCC patients with R-RT will invariably die from the disease. Survival rates have not improved in 35 years.
“The Pershing Square Sohn Prize rewards high risk/reward projects that are hard to fund through classical governmental means. Having this funding will allow us to exploit an unconventional but highly promising drug-screening platform, that of zebrafish embryos, to search for chemicals that will overcome tumor resistance to radiation therapy in patients that would otherwise likely succumb to the disease.”
To identify small-molecules that will overcome treatment resistance, we developed a genetic zebrafish model of R-RT. Zebrafish is the animal model closest to man in which unbiased, large-scale drug screens are realistically feasible. An added, crucial advantage of screening in live zebrafish is the ability to probe therapeutic efficacy and drug toxicity simultaneously. This allows to prioritize potent compounds according to their projected safety, or selectivity, in humans.
“To me, innovation begins with an unanswered question. The ability to formulate such a question starts with a vast, conceptual and technical knowledge of the field. Once with the right question in hand, I firmly believe that the approach to tackle it should remove as many preconceptions as to what the answer might be (don’t fall in love with your hypotheses!) In my lab, for instance, we screen for mutations or chemicals that produce an anticancer effect of interest while remaining completely blind, or unbiased, as to what the corresponding targets might be. Only once with the novel mutation or drug in hand do we proceed with target discovery. But beware: In a screen, you never know what you’re going to get, but you’ll get what you deserve. A lousy initial question, or an inadequate screening assay, and major disappointment will ensue. Such is the life of an innovator!”
In a recent screen of >1,100 compounds, we identified a small molecule that restores full sensitivity to RT in the zebrafish model while having no visible effect on organismal development or physiology. Using funds from PSSCRA, we will elucidate the mechanism of action of the drug and assess the strategy’s clinical potential in a large panel of human HNSCC cell lines and patient-derived xenograft (‘PDX’) mouse models. We hope to translate our discoveries into first viable treatment options for patients with radioresistant cancer.