Integrated Calendar

Despite advances in the treatment of cancer, with novel molecularly targeted therapies and drug combinations, lung cancer continues to be one of the leading causes of cancer death worldwide. For this reason, significant efforts have been made to examine the interaction between cancer and the immune system. This has led to the discovery of the programmed death 1 (PD1) and ligand (PDL1) pathway, which was found to play a key role in immune evasion by cancer cells and the formation of a tumor microenvironment. Blockade of this pathway enables the ability of the innate immune system to activate their anticancer responses and to reverse the tumor microenvironment. Newly approved drugs, such as nivolumab and pembrolizumab, have mechanisms of action that inhibit PD1, while others like atezolizumab, block PDL1. Although, responses with these drugs have shown significant activity in some patients, only 20-30% of patients respond overall. In this talk, mechanistic studies to identify predictive markers of response will be discussed along with markers of resistance (both primary and acquired). In addition, novel combinations of immunotherapy with chemotherapy, targeted therapy and even chemotherapy will be explored.

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by the adaptive alteration of another gene (the rescuer). Here we perform a genome-wide identification of SR-mediated resistance determinants by analyzing the tumor transcriptomics and survival data of 10,000 cancer patients. Predicted SR interactions are validated versus publicly available resistance data and new experimental screens that we have conducted. We show that the SR interactions successfully predict cancer patients’ response and emerging resistance and that the targeting of predicted rescuer genes re-sensitizes resistant cancer cells. These results provide novel rationale-based combinatorial approaches for proactively overcoming therapy resistance. Finally, going beyond targeted therapy, we show that the SR analysis can successfully predict molecular alterations conferring resistance to immunotherapy in melanoma patients.

[Work led by Avinash Das and Joo Sang Lee in my lab, in collaboration with the labs of Silvio Gutkind (UCSD), Cyril Benes (MGH), Keith Flaherty & Genevieve Boland (MGH) and Meenhard Herlyn (Wistar).]