Post on 26-Feb-2021
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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
BRAF > Mesenchymal
https://www.embopress.org/doi/full/10.15252/emmm.201505971
DM1N DM3N DM2N
Nestin (red) / gp100 (green)
Melanoma Heterogeneity
Grichnik JM, Burch JA, Schulteis RD, Shan S, Liu J, Darrow TL, Vervaert
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
CO
NT
RO
L
SK
ME
L28 P
+
BB
G R
x
MITF FSCN1 Composite with DAPI
E-CADHERIN (R) N-CADHERIN (G) DAPI (B)
SK
ME
L28
CO
NT
RO
L
SK
ME
L28 P
+
BB
G R
x
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
Müller J, et al. Nat Commun. 2014 Dec 15;5:5712
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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
• https://clinicaltrials.gov/ct2/show/NCT02729298?term=axl&draw=4&rank=12
#2
• To ensure elimination of a problem is to block the escape route
• Eliminate both E (TA) and M (stem) – then there maybe nowhere to hide
UV
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https://www.researchgate.net/publication/322902729_Melanin_distribution_in_human_epidermis_affords_localized_protection_against_DNA_photodamage_and_concurs_with_skin_cancer_incidence_difference_in_ex
treme_phototypes/figures?lo=1
Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.
Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge
DC, Fullam A, Alexandrov LB, Tubio JM, Stebbings L, Menzies A, Widaa S, Stratton MR, Jones PH, Campbell PJ.
Science. 2015 May 22;348(6237):880-6.
• Sun-exposed eyelid
skin
• 2-6 mutations/MB/cell
• Positively selected
‘driver’ mutations were
found in 18-32% of
normal skin cells at a
density of ~140/cm2
http://www.weather.com/health/secret-sun-damage-20130516
Science. 2015 May 22; 348(6237): 880–886. 13.2/MB
P53, NOTCH1/2/HRAS
61.2/MB
K15, PTCH1 / p53
75.8/MB
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Frequent clones of p53-mutated keratinocytes in normal human skin
• Patients w/o h/o skin cancer • Tissue from cosmetic procedures • P53 mutated clones, arising from
DEJ, 60-3,000 cells in size • Present at frequencies exceeding
40 cells per cm2 • Together involve as much as 4%
of the epidermis • More frequent in sun exposed
areas
Proc. Natl. Acad. Sci. USA Vol. 93, pp. 14025–14029, November 1996
#3
• You really are getting toasted
• UV is rewriting your skin’s genetic code – not trivially but extensively
• It’s the combination of mutations that matter
• Of course need the right cell type and in correct state as well.
https://www.pinterest.com/pin/508625351636016300/
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#4
• Declining death rate
Probability (%) of Developing Invasive Cancer during
Selected Age Intervals by Sex, US, 2012-2014
Cases and Incidence of
Melanoma by age 2014-
2016, UK #5
• It is the old white guys that are the biggest problem.
Genetics / Patterns
Spitz
HRAS
Blue
GNAQ
Lentigo
Congenital
NRAS
Acquired
BRAF
Reed
Combined
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Melanoma Dermoscopic Patterns
Sanchez MI et al. JAMA Dermatology 150:633-639, 2014
Rhomboidal – Wild type NRAS BRAF GNAQ
HRAS KIT
KIT
Dark Homogenous Streak Pattern
HRAS
GNAQ BRAF
NRAS
#6
• Germline may define mutations that develop
• Mutations drive growth pattern
• Paucity of genetic data for thin low risk tumors
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https://www.mattek.com/products/human-melanocytes/
Melanoma - Radial Disparity
KIT
AF CA AS
WT
AF CA AS
NRAS
AF CA AS
BRAF
AF CA AS
Ethnic prevalence of germline SNPs over represented in specific melanoma mutations
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
KIT
NRAS BRAF
WT
#7
• Melanoma is racially biased
• Prevention approaches may need to be modified on germline as well as environment.
Dermoscopy
Technology
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Challenges with
Melanoma Diagnosis
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Visualizing Melanoma Cells and Image Stacks in 3D
Cell is segmented Dendritic Melanoma
Cell identified Reconstruction Registration
3D
reconstructions
#8
• Confocal helps with those difficult dermoscopic diagnoses
• May help studying melanocyte/melanoma biology
Meiomitosis
• Hallmark is genomic instability
• CT antigens….meiosis proteins
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#9
• Meiotic protein expression can’t be good during mitosis.
What hasn’t changed
• Dysplastic nevi
• Sentinel node / Staging
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https://img.grepmed.com/uploads/3509/oncology-melanoma-pathophysiology-model-clark-original.png
Melanocytes
Benign Nevi
Melanomas
Melanocytic “stem cell” JID 2006;126:142-53
Melanomas do not
require pre-existing nevi
Lucas CR, Sanders LL, Murray JC, Myers SA,
Hall RP, and JM Grichnik, Early melanoma detection: non-uniform dermoscopic features and
growth, Journal of the American Academy of
Dermatology, 48(5):663-671, 2003
Dermoscopy Baseline TBP Clinical
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Dermoscopy
Baseline TBP Clinical
Melanomas are growing,
unusual and progressively
more non-uniform
Lucas CR, Sanders LL, Murray JC, Myers SA, Hall RP, and JM Grichnik, Early
melanoma detection: non-uniform dermoscopic features and growth, Journal of the
American Academy of Dermatology, 48(5):663-671, 2003
Title of Invention: Methods and systems for the detection of malignant melanoma
First named inventor: James M Grichnik
Application number: 10/858,941
Filing Date: 6/02/2004
Status: Notice of Allowance (4/18/2008)
Sentinel node Summary
• 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
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