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Cancer Progress Conference New York City Michael B. Sporn, MD - - PowerPoint PPT Presentation
Cancer Progress Conference New York City Michael B. Sporn, MD - - PowerPoint PPT Presentation
Cancer Progress Conference New York City Michael B. Sporn, MD Professor of Pharmacology and Medicine Dartmouth Medical School May 7, 2019 Statement Michael Sporn is the founder of a new company, Triterpenoid Therapeutics, whose goal is to
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Projected Huge Increase in Pancreatic Cancer Deaths, USA
2010 --- 37,000 Deaths, actual 2030 --- 63,000 Deaths, projected
- Pancreatic Cancer is projected to
be the second leading cause of cancer deaths in the USA by 2030
Rahib, L., Cancer Res 74: 2913-2921 (2014)
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Concept 1
The disease is carcinogenesis, not cancer
- Carcinogenesis is a process, not a state
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- B. Vogelstein, et al. Science 339, 1546, 2013
Process of Carcinogenesis
Progression takes many years
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Progression Model for Pancreatic Cancer
Normal PanIN-1A PanIN-1B PanIN-2 PanIN-3 Her-2/neu K-rus p16 P53 DPCA BRCA2 LOH 9P LOH 18q, 17p, 6q
Progression model for pancreatic cancer. The progression from histologically normal epithelium to low-grade PanIN to high-grade PanIN (left to right) is associated with the accumulation of specific genetic alterations (Hruban et al.,
- Am. J. Pathol., 156:1821, 2000)
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Cancer is a polygenic disease
- Pancreatic cancers contain an average
- f 63 genetic alterations
Science, 321, 1801, 2008
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Concept 2
People who are asymptomatic may not be healthy
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The concept of ‘health’ needs to consider future events, not just the immediate present
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Concept 3
Use of drugs to suppress carcinogenesis during the latency period after mutagenic initiation
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Chemoprevention Works!!!!!
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25 50 75 100 20 25 30 35 40 45 50 55 60
Arzoxifene and LG100268 Synergize in Prevention of ER- Negative Mammary Gland Tumors in MMTV-neu Mice
Weeks on diet
Percent of mice with tumors
MMTV-neu transgenic mice (Jax Labs) were fed powdered control diet or preventive agents in the same diet, beginning at 7 weeks of age. Mice (numbers shown in parentheses) were palpated weekly for tumors, and none were detected before 20 weeks of age. The experiment was terminated after mice were fed experimental diets for 60 weeks. Liby et al., Clin. Cancer Res. 12: 5902, 2006
Control Arzoxifene
(20 mg/kg diet)
LG100268
(30 mg/kg diet)
Combination
(16) (8) (8) (8)
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Complete Protection against Aflatoxin B1-Induced Liver Cancer with a Triterpenoid: DNA Adduct Dosimetry, Molecular Signature, and Genotoxicity Threshold Natalie M. Johnson, Patricia A. Egner, Victoria K. Baxter, Michael B. Sporn, Ryan S. Wible, Thomas R. Sutter, John D. Groopman, Thomas W. Kensler, and Bill D. Roebuck Cancer Prev Res; 7 July 2014 Cancer Preventi
- n
Researc h
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Complete Prevention of Liver Cancer in Rats by CDDO-Im
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Concept 8
Chemopreventive drugs may function more effectively if dosed intermittently rather than continuously
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A new paradigm for chemoprevention
Control Diet Chemopreventive agents in diet, at high doses that induce apoptosis
Carcinogen Autopsy
- M. Rendi, N. Suh, et al., Cancer Res. 64: 3566, 2004
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What we need to do
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- New Ideas
- New Diagnostic Tools
- New Drugs
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- The Old DNA
RNA Protein Model is obsolete
- A New World of Network Biology
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Fantasy and Fact in Signaling
It Ain’t So The Real World
Levy et al., Science 328, 983, 2010
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New Diagnostic Tools
- Genomic
- Proteomic
- Metabolomic
These will identify people at super high risk These will be highly profitable for Pharmas
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New Drugs
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(olives) (apples) (birch bark) (ginseng) (cork)
Triterpenoid Scaffolds
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CDDO-Me CDDO-Methyl ester CDDO-Im CDDO-Imidazolide
Oleanane Triterpenoid Drugs
CDDO-EA CDDO-Ethyl amide
O CONHCH2CH3 H O NC
O H O NC N O N O COOH H O NC O CO2Me H O NC
CDDO Liby, Sporn Pharmacol Revs 2012.
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Triterpenoids and suppression of inflammation
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- 17 -16 -15 -14 -13 -12 -11 -10 -9 -8 -7 -6
Concentration (Log M)
20 40 60 80 100 120 CDDO CDDO-Me CDDO-Im TGF-beta
Potency of Triterpenoids
CDDO-Im Suppresses iNOS Induction in Macrophages
FemtoMolar Activity of CDDO-Im
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To Upset the Apple Cart
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“Cancer is Fundamentally an Epigenetic Disease”
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“The Key Role of Epigenetics in Human Disease Prevention and Mitigation”
A.P. Feinberg, N Eng J Med 378, 1323 (2018)
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Paul Talalay