Four interdisciplinary teams of physicians and scientists from Weill Cornell Medicine have been announced as recipients of the Sandra and Edward Meyer Cancer Center's 2018 Collaborative Research Initiative grants. The awards were made in support of inter- and intra-programmatic collaborations within and across the cancer center's research programs, with the objective of generating sufficient preliminary data to transition to cancer-focused external funding. Two new Pre-R01 awards and one renewal were made in the amount of $100,000 each. A single Pre-P01/SPORE award was made in the amount of $250,000.
Harnessing the intrinsic ability of our immune system to eliminate tumors is the most promising anticancer strategy since the development of chemotherapy. This new approach, termed immunotherapy, elicits remarkable effects against melanoma and lung cancer, but patients with more aggressive tumor types such as glioblastoma, pancreatic and ovarian cancer are refractory to this strategy. Understanding how tumors inhibit the protective function of immune cells and characterizing how environmental factors and lifestyle habits influence this process is fundamental for developing more effective cancer treatments. Through funding provided by the Meyer Cancer Center, Drs. Dannenberg and Cubillos-Ruiz recently established that diet has profound effects on the progression of experimental metastatic ovarian cancer, raising the interesting possibility that tailored dietary interventions could be used to harness the anti-tumor activity of immune cells. The goal of their renewal project will be to unearth the cellular and molecular programs governed by dietary fats in cancer hosts and will deliver a mechanistic rationale for improving the effects of cancer treatments through widely accessible dietary strategies.
Clinical findings demonstrate that there is still much to be learned about the biology of Immune Checkpoint Blockade (ICB). In lung cancer, only ~20% of patients respond to ICB, and expression of PD-L1 is not a reliable biomarker for predicting response. For unknown reasons, EGR receptor (EGFR) driven lung tumors have a poor response to anti-PD-L1 therapy. Drs. McGraw and Altorki propose that a deeper understanding of PD-L1 biology will provide insight into why some tumors respond to anti-PD-L1 therapy and others do not, and why EGFR-driven tumors are resistant to ICB. The results of their studies will ultimately contribute to more effective utilization of ICB therapies as well as identify novel therapeutic targets to intercept PD-L1 checkpoint activity.
Mutations of the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in a wide range of human cancers, including 60-90% of lethal brain tumors. IDH1/2 cancer mutations hijack the enzyme to produce the oncometabolite 2-hydroxygluterate (2-HG). 2-HG reprograms the epigenome by its ability to inhibit DNA and histone demethylases. The goal of this project is to discover the mechanism by which the oncometabolite 2-hydroxygluterate (2-HG) blocks causes genome instability in IDH1/2 mutant malignancies and investigate the therapeutic sensitivity of these cancers as a consequence of defective DNA repair.
Dr. Demaria and Formenti’s Pre-SPORE program will focus on combining radiation and immunotherapy and is centered around ongoing clinical trials in both immunotherapy-sensitive (NSCLC) and resistant (prostate, breast) tumor settings. The variation in tumor settings will allow for investigation into the radiation-induced mechanisms likely to be common, as well as some that may be specific to the tumor’s genetics and its microenvironment. Composed of six projects, the program includes a variety of studies that range from hypothesis testing to hypothesis-generating. Cutting-edge technologies will be used across all projects to study the immune infiltrate and identify potential biomarkers for future patients selection as well as actionable targets to overcome resistance.