Our long-term goal is to develop therapeutic strategies that improve the survival of patients with disseminated melanoma by potentiating new and existing targeted therapies. Despite the impressive responses achieved in BRAF mutant melanoma patients treated with BRAF inhibitors, resistance inevitably occurs. A number of potential resistance mechanisms have been described, the majority of which bypass mutant BRAF through the reactivation of MAPK and PISK/AKT signaling. Although current clinical strategies are focused upon the use of BRAF inhibitors in conjunction with MEK or PISK inhibitors, the development of multiple, subtle signaling alterations at many nodes within the melanoma signaling network is likely to result in eventual resistance even to these combinations. Conceptually, we believe that the adaptive signals that mediate resistance in the majority of cases are both """"""""tumor-intrinsic"""""""", resulting from the rewiring of the melanoma signal transduction network, as well as """"""""host-derived"""""""", mediated by altered growth factor secretion and extracellular matrix from stromal fibroblasts. Our working hypothesis is that long-term abrogation of resistance will only be achieved if BF^F can be targeted in addition to multiple receptor tyrosine kinase (RTKs) and cell/matrix adhesion signals. Our preliminary studies suggest that most if not all of the signaling proteins implicated thus far in the escape from BRAF inhibitor therapy are clients of heat shock protein (HSP)-90, and we showed that inhibition of HSP90 was effective at preventing and overcoming resistance both in vitro and in vivo. In this proposal, we will use innovative phosphoproteomic- and chemical proteomic-based systems biology approaches to define the HSP """"""""clientome"""""""" that drives intrinsic and acquired resistance of melanomas to MAPK pathway inhibition (BRAF, MEK and BRAF+MEK). We will further investigate the role of fibroblast-derived signals in remodeling the HSP-clientome of melanoma cells and will determine how this allows the tumor to escape MAPK inhibitor-mediated apoptosis. Pre- and post-treatment biopsies from melanoma patients receiving a BRAF and HSP90 inhibitor combination (vemurafenib+XL888) will be analyzed to look for patterns of HSP client protein degradation associated with long-term therapeutic response. Together, these studies are expected to give a systems level view of how melanoma cells resist MAPK pathway inhibition and will provide new paradigms to overcome drug resistance in melanoma.
Although small molecule inhibitors of BRAF and MEK and the BRAF+MEK inhibitor combination are showing great promise as novel melanoma therapies, their effectiveness is severely limited by both acquired and intrinsic drug resistance. The aim of the proposal is to use phospho-proteomics, chemical proteomics and network modeling to identify the key mechanisms of therapeutic escape and to perform preclinical experiments and to analyze specimens from an ongoing phase I clinical trial to determine whether inhibition of HSP90 abrogates the onset of BRAF inhibitor resistance.
|Strom, Tobin; Harrison, Louis B; Giuliano, Anna R et al. (2017) Tumour radiosensitivity is associated with immune activation in solid tumours. Eur J Cancer 84:304-314|
|Faião-Flores, F; Alves-Fernandes, D K; Pennacchi, P C et al. (2017) Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells. Oncogene 36:1849-1861|
|Zhu, Genyuan; Falahat, Rana; Wang, Kui et al. (2017) Tumor-Associated Tertiary Lymphoid Structures: Gene-Expression Profiling and Their Bioengineering. Front Immunol 8:767|
|Wan, Lixin; Chen, Ming; Cao, Juxiang et al. (2017) The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function. Cancer Discov 7:424-441|
|Markowitz, Joseph; Wang, Jiang; Vangundy, Zach et al. (2017) Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration. Sci Rep 7:15424|
|Yagawa, Yohsuke; Robertson-Tessi, Mark; Zhou, Susan L et al. (2017) Systematic Screening of Chemokines to Identify Candidates to Model and Create Ectopic Lymph Node Structures for Cancer Immunotherapy. Sci Rep 7:15996|
|Li, Jiannong; Smalley, Inna; Schell, Michael J et al. (2017) SinCHet: a MATLAB toolbox for single cell heterogeneity analysis in cancer. Bioinformatics 33:2951-2953|
|Niessner, Heike; Sinnberg, Tobias; Kosnopfel, Corinna et al. (2017) BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma. Clin Cancer Res 23:6203-6214|
|Wang, Daniel Y; Eroglu, Zeynep; Ozgun, Alpaslan et al. (2017) Clinical Features of Acquired Resistance to Anti-PD-1 Therapy in Advanced Melanoma. Cancer Immunol Res 5:357-362|
|Robinson, James P; Rebecca, Vito W; Kircher, David A et al. (2017) Resistance mechanisms to genetic suppression of mutant NRAS in melanoma. Melanoma Res 27:545-557|
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