9/18/2019 1 Update on Melanoma James M. Grichnik M.D. Ph.D. Disclosures • Galileo Group (Consulting) • Canfield Scientific (Consulting) • DigitalDerm (Founder, Major Shareholder) • 12/2015 CaliberID (Equipment and meeting support) Outline • Immune Regulation - Microbiome • Targeted RX - Phenotype Switching • UV – not trivial • Genetics: Melanoma Patterns • Melanoma - Radial Disparity • Technology – Confocal • What hasn’t significantly changed - Dysplastic nevi vs Melanoma progression - Sentinel node Immune Regulation
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Update on Melanoma - SEC MeetingsVisualizing Melanoma Cells and Image Stacks in 3D Cell is segmented Dendritic Melanoma Cell identified Registration Reconstruction 3D reconstructions
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9/18/2019
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Update on Melanoma James M. Grichnik M.D. Ph.D.
Disclosures
• Galileo Group (Consulting)
• Canfield Scientific (Consulting)
• DigitalDerm (Founder, Major Shareholder)
• 12/2015 CaliberID (Equipment and meeting support)
Outline • Immune Regulation - Microbiome
• Targeted RX - Phenotype Switching
• UV – not trivial
• Genetics: Melanoma Patterns
• Melanoma - Radial Disparity
• Technology – Confocal
• What hasn’t significantly changed
- Dysplastic nevi vs Melanoma progression
- Sentinel node
Immune Regulation
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Checkpoint Inhibitors
Engl J Med. 2015 July 02; 373(1): 23–34. doi:10.1056/NEJMoa1504030
Microbiome Fecal Diversity
Gopalakrishnan et al., Science 359, 97–103 (2018)
Bacterial Types
Gopalakrishnan et al., Science 359, 97–103 (2018)
CD8+ density
Gopalakrishnan et al., Science 359, 97–103 (2018)
Transplantable
Gopalakrishnan et al., Science 359, 97–103 (2018)
Bacteriophages
Diagnostic Potential and Interactive Dynamics of the Colorectal Cancer Virome. Hannigan GD, Duhaime MB, Ruffin MT 4th, Koumpouras CC, Schloss PD. MBio. 2018 Nov 20;9(6). pii: e02248-18.
Human Virome and Disease: High-Throughput Sequencing for Virus Discovery, Identification of Phage-Bacteria Dysbiosis and Development of
Therapeutic Approaches with Emphasis on the Human Gut. Santiago-Rodriguez TM, Hollister
EB. Viruses. 2019 Jul 18;11(7). pii: E656.
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Opportunities
• Stool
• Blood
• Oral
• Weight
• Gender
#1
• Mom was right - eat your vegetables
Targeted RX
Development of encorafenib for BRAF-mutated advanced melanoma. Koelblinger P, Thuerigen O, Dummer R. Curr Opin Oncol. 2018 Mar;30(2):125-133
CE, and HF Seigler, Melanoma, a tumor based on a mutant stem cell?,
Journal of Investigative Dermatology, 126:143-153, 2006
PANX1 inhibition with probenecid down regulates MITF/gp100
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MITF (G) FSCN1 (R) DAPI (B)
SK
ME
L28
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MITF FSCN1 Composite with DAPI
E-CADHERIN (R) N-CADHERIN (G) DAPI (B)
SK
ME
L28
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E-Cadherin N-Cadherin Composite with DAPI
Dominant role of the niche in melanocyte stem-cell fate determination
Nishimura EK, Jordan SA, Oshima H, Yoshida H, Osawa M, Moriyama M, Jackson IJ, Barrandon Y, Miyachi Y, Nishikawa S. Nature. 2002 Apr 25;416(6883):854-60.
Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma
Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Müller J, et al. Nat Commun. 2014 Dec 15;5:5712 Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Müller J, et al. Nat Commun.
2014 Dec 15;5:5712
AXL Inhibitor
• TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers.
• Preclinical studies have shown promising antitumor activity of TP-0903 as a single agent against a variety of tumor types in both in vitro and in vivo studies.
• Have BRAF-mutated melanoma that has not responded to immunotherapy or a combination BRAF/MEK inhibitor