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. Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma
  2. Correction: In vivo E2F reporting reveals efficacious schedules of MEK1/2–CDK4/6 targeting and mTOR–s6 resistance mechanisms (Cancer Discovery, 2018, 8, 1654)
  3. ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma
  4. BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association
  5. Playing the melanoma endgame
  6. ErbB3 targeting enhances the effects of MEK inhibitor in wild-type BRAF/NRAS melanoma
  7. The Autophagy Receptor Adaptor p62 is Up-regulated by UVA Radiation in Melanocytes and in Melanoma Cells
  8. In vivo E2F reporting reveals efficacious schedules of MEK1/2–CDK4/6 targeting and mTOR–s6 resistance mechanisms
  9. A preexisting rare PIK3CAe545ksubpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling
  10. Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma
  11. Erratum: Publisher Correction: ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma (Nature communications (2018) 9 1 (28))
  12. Novel therapeutic strategies and targets in advanced uveal melanoma
  13. CKS1 expression in melanocytic nevi and melanoma
  14. Response and resistance to paradox-breaking BRAF inhibitor in melanomas in vivo and Ex vivo
  15. A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma
  16. “If you want to go far, go together”
  17. Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis
  18. Inhibition of age-related therapy resistance in melanoma by rosiglitazone-mediated induction of klotho
  19. Dysregulated GPCR signaling and therapeutic options in uveal melanoma
  20. Co-Targeting HGF/cMET Signaling with MEK Inhibitors in metastatic uveal melanoma