J. Silvio Gutkind, Ph.D. UCSD Moores Cancer Center Basic Science of Premalignancy: Opportunities for Precision Cancer Prevention
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1 J. Silvio Gutkind, Ph.D. UCSD Moores Cancer Center Basic Science of Premalignancy: Opportunities for Precision Cancer Prevention February 3-5, 2016 Lansdowne Resort, Leesburg, VA
2 Chemoprevention Risk Benefit A molecular revolution: Molecular and cellular mechanisms Identify patients at risk (Premalignant Cancer Genome) Intersect (Precision Cancer Prevention) (Mechanistic Biomarkers) Challenges and opportunities
3 Cancer Prevention: Targeting mtor progression ~90% human HNSCC activation HPV - and HPV + Forastiere, Sidransky, et al., N Engl J Med 2001;345:
4 Cancer Prevention: Targeting mtor progression ~90% human HNSCC activation HPV - and HPV + Activity of mtor inhibition with Rapamycin in: Multiple genetically-defined oral models carcinogenesis models Recently completed Phase I/II Neoadjuvant trial in newly diagnosed HNSCC patients
5 progression Oncogenic stress (mtor activation) mtor activation in the basal layer of stratified oral epithelium (% of ps6 + cells ± SEM) Iglesias-Bartolome, et al., Cell Stem Cell, ±0.6 (n=95) 12.3±1.1 (n=130) 86.5±6.3 (n=175) 100 (n=500) William, Lippman, Gutkind, Molinolo, et al., unpublished
6 progression Oncogenic stress (mtor activation) mtor activation in the basal layer of stratified oral epithelium (% of ps6 + cells ± SEM) Iglesias-Bartolome, et al., Cell Stem Cell, ±0.6 (n=95) 12.3±1.1 (n=130) 86.5±6.3 (n=175) 100 (n=500) William, Lippman, Gutkind, Molinolo, et al., unpublished
7 progression Oncogenic stress (mtor activation) 11-36% progress Premalignant Cancer Genome 64-89% do not progress William, Lippman et al., unpublished. Iglesias-Bartolome, et al., Cell Stem Cell, 2012
8 progression Premalignant Cancer Genome Oncogenic stress (mtor activation) Immune evasion (PD-L1, TAMs MDSCs) Intersect: Identify and exploit systems vulnerabilities 11-36% progress Precision Cancer Prevention Immune intervention Chemoprevention 64-89% do not progress Iglesias-Bartolome, et al., Cell Stem Cell, 2012
9 Repurposing Metformin Cancer Prevention Decreases mtor Preclinical oral initiation models (HPV - and HPV + ) Epidemiological data M4OC-Prevent: NC1 N01 Phase IIa Metformin Trial for Cancer Prevention (NCT ) Premalignant Cancer Genome Intersect: Identify and exploit systems vulnerabilities Precision Cancer Prevention Immune intervention Chemoprevention Understand mechanism of action
10 Metformin activity Systemic Metabolic Decrease insulin/igf1 Microenvironment (immune cells) Microbiome Cancer initiating cells mtor (activation/sensitivity) OCT3 (transporter) LKB1 (mutations/loss) mtdna mutations Others? Premalignant Cancer Genome Intersect: Identify and exploit systems vulnerabilities Precision Cancer Prevention Immune intervention Chemoprevention Understand mechanism of action Define mechanistic biomarkers of therapeutic response
11 Basic and Translational Science: Opportunities for Precision Cancer Prevention Molecular Revolution: Molecular and cellular mechanisms (Premalignant Cancer Genome) The fight against is a team effort! Thank you! Intersect: Effective, safe, low cost preventive strategies (Precision Cancer Prevention) (Mechanistic Biomarkers) Premalignant Cancer Genome Intersect: Identify and exploit systems vulnerabilities Precision Cancer Prevention Immune intervention Chemoprevention Understand mechanism of action Define mechanistic biomarkers of therapeutic response
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