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February 3-5, 2016 | Lansdowne Resort, Leesburg, VA
J. Silvio Gutkind, Ph.D.
UCSD Moores Cancer Center
Basic Science of Premalignancy:
Opportunities for Precision Cancer Prevention
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
Oral Cancer Prevention: Targeting mTOR
Oralcancer
Normal Hyperplasia Dysplasia(OPL)
Oral cancer progression(e.g., tongue OSCC)
Forastiere, Sidransky, et al., N Engl J Med 2001;345:1890-1900.
~90% human HNSCC
activation
HPV- and HPV+
Oral Cancer Prevention: Targeting mTOR
Oralcancer
Normal Hyperplasia Dysplasia(OPL)
Oral cancer progression(e.g., tongue OSCC)
~90% human HNSCC
activation
HPV- and HPV+
Activity of mTOR inhibition with Rapamycin in:
• Multiple genetically-defined oral cancer models
• Oral carcinogenesis models
• Recently completed Phase I/II Neoadjuvant trial in newly diagnosed HNSCC
patients
Oral Cancer Prevention: Targeting mTOR in oral premalignancy
Oralcancer
Normal Hyperplasia Dysplasia(OPL)
Oncogenic stress
(mTOR activation)
Iglesias-Bartolome, et al., Cell Stem Cell, 2012
• Protect normal stem cells:• DDS response • First line of defense against
cancer
Oral cancer progression(e.g., tongue OSCC)
mTOR activation in the basal layer
of stratified oral epithelium (% of pS6+ cells ± SEM)
William, Lippman, Gutkind, Molinolo, et al., unpublished
3.0±0.6
(n=95)
86.5±6.3
(n=175)
100
(n=500)
12.3±1.1
(n=130)
Oral cancer
Normal Hyperplasia Dysplasia(OPL)
Oncogenic stress
(mTOR activation)
Iglesias-Bartolome, et al., Cell Stem Cell, 2012
Oral cancer progression(e.g., tongue OSCC)
• Protect normal stem cells:• DDS response • First line of defense against
cancer
Oral Cancer Prevention: Targeting mTOR in oral premalignancy
mTOR activation in the basal layer
of stratified oral epithelium (% of pS6+ cells ± SEM)
William, Lippman, Gutkind, Molinolo, et al., unpublished
3.0±0.6
(n=95)
86.5±6.3
(n=175)
100
(n=500)
12.3±1.1
(n=130)
Oralcancer
Normal Hyperplasia Dysplasia(OPL)
Oral cancer progression(e.g., tongue OSCC)
Oncogenic stress
(mTOR activation)
Iglesias-Bartolome, et al., Cell Stem Cell, 2012
11-36% progress
64-89% do not progress
• Protect normal stem cells:• DDS response • First line of defense against
cancer
• Identify patients at risk: • Premalignant Cancer Genome
William, Lippman et al.,
unpublished.
Oral Cancer Prevention: Targeting mTOR in oral premalignancy
11-36% progress
64-89% do not progress
Oralcancer
Normal Hyperplasia Dysplasia(OPL)
Oral cancer progression(e.g., tongue OSCC)
Oncogenic stress
(mTOR activation)
• Protect normal stem cells:• DDS response • First line of defense against
cancer
• Identify patients at risk: • Premalignant Cancer Genome
• Intersect: • Identify and exploit systems
vulnerabilities • Precision Cancer Prevention
• Immune intervention• Chemoprevention
Immune evasion(PD-L1, TAMs
MDSCs)
Oral Cancer Prevention: Targeting mTOR in oral premalignancy
Iglesias-Bartolome, et al., Cell Stem Cell, 2012
• Protect normal stem cells:• DDS response • First line of defense against
cancer
• Identify patients at risk: • Premalignant Cancer Genome
• Intersect: • Identify and exploit systems
vulnerabilities • Precision Cancer Prevention
• Immune intervention • Chemoprevention• Understand mechanism of
action
Oral Cancer Prevention: Targeting mTOR in oral premalignancy
Repurposing Metformin
Oral Cancer Prevention• Decreases mTOR• Preclinical oral cancer
initiation models (HPV- and HPV+)
• Epidemiological data
• M4OC-Prevent:NC1 N01 Phase IIaMetformin Trial for Oral Cancer Prevention(NCT01195922)
• Protect normal stem cells:• DDS response • First line of defense against
cancer
• Identify patients at risk: • 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
Metformin activitySystemic• Metabolic• Decrease insulin/IGF1• Microenvironment
(immune cells)• Microbiome
Cancer initiating cells• mTOR (activation/sensitivity)• OCT3 (transporter)• LKB1 (mutations/loss)• mtDNA mutations• Others?
Oral Cancer Prevention: Targeting mTOR in oral premalignancy
Basic and Translational Science:
Opportunities for Precision Cancer Prevention
Molecular Revolution:
• Molecular and cellular mechanisms
• Identify patients at risk:(Premalignant Cancer Genome)
• Intersect:Effective, safe, low cost preventive strategies(Precision Cancer Prevention)(Mechanistic Biomarkers)
The fight against cancer
is a teameffort!
Thank you!
• Protect normal stem cells:• DDS response • First line of defense against
cancer
• Identify patients at risk: • 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
