To improve therapeutic strategies, we propose to dissect primary (intrinsic) resistance of a given melanoma to a panel of inhibitors with distinct modes of action. Our preliminary studies demonstrate that following a given drug treatment, melanoma cells not only enter apoptosis and necrosis, but they can also respond via one of two senescent phenotypes. These include either a "natural" irreversible (terminal) senescence, or a second type of senescence that we have recently observed, which, while bearing the hallmarks of classical senescence, is reversible. Due to the fact that this reversible senescence can have tumor-protective properties and give rise to a proliferative population, we term it "pseudo" senescence. This proposal is designed to define the role of therapy-induced senescence in melanoma and to develop novel therapeutic strategies that promote irreversible senescence and sensitize cells to therapy-induced apoptosis. In the first aim we will define therapy-induced senescence and will determine the molecular mechanisms underlying the heterogeneous responses to signaling modulators/inhibitors, including novel BRAF dimer inhibitors. It is likely that each type of senescence will have different outcomes, ranging from eventual cell death to the increase of invasion followed by re-growth. Our studies will assess the different cell fates to best define the mechanisms leading to the terminal senescence, and ultimately, cell death in combination with other reagents. In the second aim, we will develop therapeutic strategies for maximizing the induction of senescence/cell death in melanomas. We will test the hypothesis that pro-survival autophagy modulates the long-term responses to senescence induction and will develop combination therapies to induce irreversible senescence.

Public Health Relevance

This proposal addresses the question why not all cancer cells within a tumor that are positive for the BRAF mutation are being killed. Besides dying when exposed to BRAF inhibitors, we have defined a senescence state, pseudo-senescence, where cells are just dormant and can recover to then grow again. We intend to molecularly dissect the two different senescence states and develop combination therapies that drive cells into irreversible senescence while disallowing cells to enter the pseudo-senescence state.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA114046-07
Application #
8759671
Study Section
Special Emphasis Panel (ZCA1-RPRB-2)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
$460,322
Indirect Cost
$131,803
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Webster, Marie R; Xu, Mai; Kinzler, Kathryn A et al. (2015) Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells. Pigment Cell Melanoma Res 28:184-95
Leu, Julia I-Ju; Zhang, Pingfeng; Murphy, Maureen E et al. (2014) Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket. ACS Chem Biol 9:2508-16
Vultur, A; Villanueva, J; Krepler, C et al. (2014) MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 33:1850-61
Streib, Manuel; Kraling, Katja; Richter, Kristin et al. (2014) An organometallic inhibitor for the human repair enzyme 7,8-dihydro-8-oxoguanosine triphosphatase. Angew Chem Int Ed Engl 53:305-9
Ma, Xiao-Hong; Piao, Sheng-Fu; Dey, Souvik et al. (2014) Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 124:1406-17
Zhang, Pingfeng; Leu, Julia I-Ju; Murphy, Maureen E et al. (2014) Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate. PLoS One 9:e103518
Wang, Tao; Ge, Yingbin; Xiao, Min et al. (2014) SECTM1 produced by tumor cells attracts human monocytes via CD7-mediated activation of the PI3K pathway. J Invest Dermatol 134:1108-18
Malecka, Kimberly A; Fera, Daniela; Schultz, David C et al. (2014) Identification and characterization of small molecule human papillomavirus E6 inhibitors. ACS Chem Biol 9:1603-12
Licciulli, Silvia; Maksimoska, Jasna; Zhou, Chun et al. (2013) FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem 288:29105-14
Kastl, Anja; Dieckmann, Sandra; Wahler, Kathrin et al. (2013) Rhenium complexes with visible-light-induced anticancer activity. ChemMedChem 8:924-7

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