Melanoma is noted for its alarming increase in incidence, especially amongst the young, aggressive clinical behavior and propensity for lethal metastasis, illustrating an urgent need for new treatment strategies for this disease. Despite the bleak clinical and epidemiological picture, genetic analysis has uncovered key driver oncogenes in melanoma such as mutationally activated BRAF. Indeed, when the BRAFV600E oncoprotein is pharmacologically inhibited with vemurafenib, BRAF mutated melanoma patients, even those with widely disseminated, metastatic disease, have enjoyed dramatic tumor regression coupled with significant health improvement. However, since not all BRAF mutated melanoma patients respond to vemurafenib and, those that do, generally relapse with lethal drug resistant disease, the paradigm of melanoma therapy is evolving towards rationally-targeted combinations of pathway-targeted inhibitors acting against BRAFV600E and cooperating signaling modules such as the PI3'-kinase->AKT pathway. Indeed, despite vemurafenib's clinical success and our growing scientific knowledge of the melanoma cell's inner workings, the challenge remains how best to employ BRAF inhibitors for melanoma therapy to: 1. Maximize therapeutic benefit; 2. Minimize emergence of lethal drug resistant disease; and; 3. Mitigate potentially harmful side effects. Consequently, the long-term, overarching goal of this research is to design BRAF inhibitor-based combination therapies that enhance the overall response rate and the depth of each patient's primary anti-tumor response and extend indefinitely the duration of remission of patients with BRAF mutated melanoma in collaboration with colleagues in the UCSF Melanoma Clinic. Towards these goals, the short-term aims of this proposal are to employ state-of-the-art genetically engineered mouse (GEM) models, bona fide human melanoma cells and a portfolio of clinically relevant pathway-targeted inhibitors to elucidate the molecular mechanism(s) of BRAFV600E/PI3'- kinase pathway cooperation in melanomagenesis and the consequences of combined pathway-targeted blockade in the pre-clinical setting.
In Aim 1, GEM models will be used to probe the importance of PI3'- kinase->AKT signaling in cooperating with oncogenic BRAFV600E in converting normal melanocytes to metastatic melanoma cells.
In Aim 2 the superiority of combined versus single agent inhibition of BRAFV600E or PI3'-kinase in promoting tumor regression will be evaluated using GEM models of BRAFV600E-initiated melanoma. To complement analysis of mouse melanoma specimens in Aim 2, a panel of bona fide human BRAFV600E expressing melanoma cell lines will be employed in Aim 3 to elucidate molecular mechanism(s) by which BRAFV600E cooperates with PI3'-kinase->AKT signaling in regulating the melanoma cell division cycle and/or apoptosis through effects on protein synthesis. When completed, these studies will provide the mechanistic foundation for the development of robust and rational, pathway-targeted combination therapeutic strategies to increase both the quantity and quality of life of patients with BRAF mutated melanoma.
Melanoma is an increasingly common and highly aggressive form of cancer diagnosed in ~132,000 patients and responsible for ~20,000 deaths per year worldwide. Recently a new drug, vemurafenib, has shown great promise in the treatment of the ~50% of patients whose melanoma is driven by a mutated BRAF oncogene. Leveraging the success of vemurafenib, we propose here to employ state-of-the-art experimental systems to design and evaluate new, rationally targeted combination therapeutic strategies with the long-term goal of curing patients with melanoma.
| Rauen, Katherine A; Schoyer, Lisa; Schill, Lisa et al. (2018) Proceedings of the fifth international RASopathies symposium: When development and cancer intersect. Am J Med Genet A 176:2924-2929 |
| Silva, Jillian M; Deuker, Marian M; Baguley, Bruce C et al. (2017) PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation. Pigment Cell Melanoma Res 30:353-367 |
| Sakamoto, Naoya; Feng, Ying; Stolfi, Carmine et al. (2017) BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis. Elife 6: |
| Merlino, Glenn; Herlyn, Meenhard; Fisher, David E et al. (2016) The state of melanoma: challenges and opportunities. Pigment Cell Melanoma Res 29:404-16 |
| van Veen, J Edward; Pringle, Daphne R; McMahon, Martin (2016) P2A-Fluorophore Tagging of BRAF Tightly Links Expression to Fluorescence In Vivo. PLoS One 11:e0157661 |
| Grossauer, Stefan; Koeck, Katharina; Murphy, Nicole E et al. (2016) Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model. Oncotarget 7:75839-75853 |
| Cho, Joseph H; Robinson, James P; Arave, Rowan A et al. (2015) AKT1 Activation Promotes Development of Melanoma Metastases. Cell Rep 13:898-905 |
| Deuker, Marian M; Marsh Durban, Victoria; Phillips, Wayne A et al. (2015) PI3'-kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma. Cancer Discov 5:143-53 |
| McMahon, Martin (2015) Intermittent dosing in melanoma. Clin Adv Hematol Oncol 13:348-50 |
| Mann, Michael B; Black, Michael A; Jones, Devin J et al. (2015) Transposon mutagenesis identifies genetic drivers of Braf(V600E) melanoma. Nat Genet 47:486-95 |
Showing the most recent 10 out of 23 publications
