Philadelphia University + Thomas Jefferson University

Aplin, Andrew

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Andrew E. Aplin, PhD

Contact Dr. Aplin

233 South 10th Street
Room 522
Philadelphia, PA 19107

(215) 503-7296
(215) 923-9248 fax

Research & Clinical Interests

Melanoma arises from epidermal melanocytes, the pigment producing cells in the skin, or their progenitors. Currently, melanoma metastasis is only preventable by early detection and surgical excision of primary tumors; hence, there is an immediate need to understand the mechanisms underlying melanocyte transformation. We utilize molecular and clinical grade inhibitor approaches to alter key signaling pathway in primary human melanocytes and a panel of melanoma cells characterizing different stages of melanoma progression. We test the role of target proteins in 3D skin mimetic in vitro systems and an intradermal in vivo imaging model.

The serine/threonine kinase, B-RAF, is somatically mutated in ~60% of melanomas. Mutant B-RAF hyper-activates signaling, which is required for melanoma growth and invasion. One focus in the laboratory is determining the effectors of mutant B-RAF signaling that elicit malignant traits in melanoma cells. We have shown a role for Bcl-2 family proteins and integrin-mediated adhesion in the survival properties of melanoma cells, and a function for the GTPase, Rnd3, in cell invasion and migration in 3D. Recently, we have identified a stemness factor, FOXD3, which is up-regulated in mutant B-RAF melanoma cells following targeting of the mutant B-RAF signaling pathway. We are currently investigating the role of up-regulated FOXD3 in melanoma. Ultimately, we expect to identify the mechanisms underlying invasive growth of melanomas and, in doing so, identify novel targets for therapeutic intervention.

Clinical trials utilizing RAF inhibitors in late-stage mutant B-RAF melanoma patients are underway. The majority of patients enrolled in a recent RAF inhibitor trials showed dramatic clinical responses. Unfortunately, most of the original responders are now eliciting drug resistance. This acquired/secondary resistance is a major obstacle to the prolonged effects of kinase inhibitor therapies. We are elucidating modes of resistance to RAF inhibitors with the view that identifying novel RAF inhibitor resistance mechanisms will direct new combinatorial trials for melanoma.

Publications

Most Recent Peer-Reviewed Publications

  1. A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma
  2. “If you want to go far, go together”
  3. Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis
  4. Inhibition of age-related therapy resistance in melanoma by rosiglitazone-mediated induction of klotho
  5. Dysregulated GPCR signaling and therapeutic options in uveal melanoma
  6. Co-Targeting HGF/cMET Signaling with MEK Inhibitors in metastatic uveal melanoma
  7. Running INTERFERONce on immunotherapy
  8. The Autophagy Receptor Adaptor p62 is Up-regulated by UVA Radiation in Melanocytes and in Melanoma Cells
  9. An in vivo reporter to quantitatively and temporally analyze the effects of CDK4/6 inhibitor-based therapies in melanoma
  10. Triple jeopardy for people with albinism
  11. The melanoma field with dendritic roots
  12. The state of melanoma: challenges and opportunities
  13. Targeting mutant NRAS signaling pathways in melanoma
  14. Of Mice and melanoma: PDX system for modeling personalized medicine
  15. Welcome to the New Year!
  16. MIG6 Is MEK Regulated and Affects EGF-Induced Migration in Mutant NRAS Melanoma
  17. Establishment and Characterization of Orthotopic Mouse Models for Human Uveal Melanoma Hepatic Colonization
  18. The Broad Stroke of Hsp90 Inhibitors: Painting over the RAF Inhibitor Paradox
  19. Fibroblast-derived neuregulin 1 promotes Compensatory ErbB3 receptor signaling in mutant BRAF melanoma
  20. PAX3 and FOXD3 promote CXCR4 expression in melanoma