OVERALL ABSTRACT This is the A1 re-submission of a new Program Project Grant (PPG) focused on studying how advanced melanoma resists targeted therapies and immunotherapies, either upfront or after a period of response, and this information is aimed at defining the vulnerabilities that provide new therapeutic opportunities. Project 1 (Roger Lo) focuses on the study of resistance of NRASMUT melanomas to targeted therapies and immunotherapies. Studies will focus on discovering and co-targeting genomic, epigenomic and/or signaling alterations causative of MEK inhibitor (MEKi) resistance; exploiting MEKi-addiction of MEKi-resistant clones; and identifying immune targets to augment MEKi efficacy and suppress MEKi resistance in vivo in NRASMUT melanomas. Project 2 (Thomas Graeber) focuses on studying molecular mechanisms and targeting of the ferroptosis sensitivity of dedifferentiated melanomas in preclinical models. In addition, this project will also define and target master regulatory programs underlying melanoma dedifferentiation. Project 3 (Antoni Ribas) focuses on studying primary and acquired resistance to PD-1 blockade immunotherapy, especially defining mutations in the interferon gamma and antigen presentation pathways, as well as reversing T cell exclusion from cancers. The understanding of these resistance mechanisms will rationalize combinatorial therapies to be tested in preclinical mouse models. The three projects are supported by three cores, the Administrative and Statistics Core (Antoni Ribas), the Biospecimen Core (Begonya Comin-Anduix) and the Patient-Derived Xenograft (PDX)/Syngeneic Mouse Core (Gatien Moriceau). The proposed research addresses scientific problems that require integrated and collaborative teamwork. In Project 1, the study of MAPK inhibitor addiction, resulting in sensitivity to drugs that induce parthanatos (a caspase-independent mode of cell death), can be applied to the melanoma dedifferentiation states studied in Project 2 and will synergize with immunotherapies studied in Project 3. Similarly, in Project 2, the dedifferentiated melanoma phenotype, which is a resistance mechanism to MAPK inhibitors and also induced by T cell-released cytokines, leads to sensitivity to ferroptosis- (an iron-dependent form of nonapoptotic cell death) inducing agents. This resistance mechanism will be explored in NRAS mutant melanoma in Project 1 and across melanoma with resistance to anti-PD1 in Project 3. Reciprocally, Project 3 will seek to integrate the new concepts and models from Projects 1 and 2, given the likely immune effects of inducing these new forms of cell death. This collaborative research will require sharing the patient-derived tissues, model systems, and therapeutic regiments acquired and developed in each Project, facilitated by Cores B and C, and statistical design and support from Core A. 1
The remarkable progress that has been made within the past decade in the treatment of advanced melanoma has been based on a deep understanding of biology and has resulted in unprecedented clinical benefits. Further understanding of mechanisms of response and resistance and uncovering specific cancer vulnerabilities, will enable the development of improved therapies. We anticipate that the knowledge gained from this program project grant and its three research projects will provide benefits to patients with other cancers. 1
