Identification of mutations in receptor and non-receptor protein kinases that drive malignant transformation of cancer cells ('driver' mutations) have revolutionized patient care by opening the door to patient-tailored targeted therapies that can improve patient survival. In order to discover new targets for therapy, we sequenced the coding regions of -100 melanomas and identified a large number of somatic mutations and inherited Single Nucleotide Variants (SNVs). One of the most important findings of this effort is the identification ofthe RAC1 signaling pathway as a potential new target for melanoma therapy. The analysis revealed a recurrent, UV signature activating mutation in this RHO family of small GTPases, RAC[P29S], in ~5% of melanomas, in addition, the sequencing data revealed mutations in upstream regulators and downstream effectors of RAC1 pathway in a large numbers of melanoma tumors. Functional studies demonstrated an important role in proliferation and migration of not only mutant but also melanoma cells that that donot harbor the P29S mutation. The data suggest that pharmacological inhibition of RACl or its critical effeGtor(s) can be applied for development of new therapies for melanoma patients. The general goals ofthis project are to determine the frequency and prognostic significance of RAC[P29S] mutation in sun exposed melanocytic lesions, and to identify downstream effectors of RACl most likely to be druggable targets in this pathway.
The specific aims are:
Aim 1 : To determine the frequency of RAC1[P29S] mutation and RACl expression levels in a large cohort of melanocytic lesions and correlate with pathological features and tumor progression;
Aim 2 : To elucidate the downstream targets of activated RACl in melanomas.
Aim 3 : To identify small-molecule inhibitors of PAK kinases, the RACl effectors. These studies are likely to provide new opportunities for drug discovery for melanomas and possibly other cancers that can facilitate patienttailored targeted therapy.
There is a need for new patient-tailored therapy for melanoma. Treatment of melanoma patients carrying BRAF[V600E/K] mutations with vemurafenib (PLX4032/RG7204), renamed Zelboraf, yields a very high response rate, but the disease tends to relapse. The novel regulatory pathway discovered by exome sequencing and validated by functional analyses provides the opportunity for additional therapeutic targets for patients who do not benefit from current therapies.
| Ferrucci, Leah M; Cartmel, Brenda; Clare, Rachel A et al. (2018) Cross-sectional assessment of ultraviolet radiation-related behaviors among young people after a diagnosis of melanoma or basal cell carcinoma. J Am Acad Dermatol 79:149-152 |
| Arbesman, Joshua; Ravichandran, Sairekha; Funchain, Pauline et al. (2018) Melanoma cases demonstrate increased carrier frequency of phenylketonuria/hyperphenylalanemia mutations. Pigment Cell Melanoma Res 31:529-533 |
| Perry, Curtis J; Muñoz-Rojas, Andrés R; Meeth, Katrina M et al. (2018) Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. J Exp Med 215:877-893 |
| Liu, Xiaoni; Zhang, Shang-Min; McGeary, Meaghan K et al. (2018) KDM5B Promotes Drug Resistance by Regulating Melanoma Propagating Cell Subpopulations. Mol Cancer Ther : |
| Sulkowski, Parker L; Scanlon, Susan E; Oeck, Sebastian et al. (2018) PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF. Mol Cancer Res 16:1241-1254 |
| Chen, Ling; Azuma, Takeshi; Yu, Weiwei et al. (2018) B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction. Proc Natl Acad Sci U S A 115:3126-3131 |
| Krauthammer, Michael (2018) Unraveling the etiology of primary malignant melanoma of the esophagus. J Thorac Dis 10:S1074-S1075 |
| Das, Rituparna; Bar, Noffar; Ferreira, Michelle et al. (2018) Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest 128:715-720 |
| Weed, Jason; Gibson, Juliet; Lewis, Julia et al. (2017) FISH Panel for Leukemic CTCL. J Invest Dermatol 137:751-753 |
| Zhang, Yanchang; Cartmel, Brenda; Choy, Courtney C et al. (2017) Body mass index, height and early-onset basal cell carcinoma in a case-control study. Cancer Epidemiol 46:66-72 |
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