Improvements in cure: The model
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1 Head and neck service: Century of progress Bhuvanesh Singh, M.D., Ph.D. Attending Surgeon Director, Laboratory of Epithelial Cancer Biology Director, Speech and Hearing Center Memorial Sloan-Kettering Cancer Center Improvements in cure: The model Rizvi N A et al. Clin Cancer Res 2011;17:
2 Approach to genetic analysis Impact of genetics on treatment of head and neck cancer Preventative surgery RET mutation Extent of surgery Molecular margins Sentinel node biopsy/analysis Selecting treatment Chemoresponse prediction Adjuvant treatment Ganley,..,Singh. JCO 2006 Wreesman,..,Singh, JCO 2007 Tumor diameter (mm) 100 Time line for cancer development Tumor first visible on imaging(10 8 cells) Death (10 12 cells) Tumor first palpable (10 8 cells) Years Factors predisposing to the accumulation of genetic events Environmental Inherited factors Cancer Carcinogens Tobacco/Alcohol HPV Genetic syndromes Kutler.Singh. JNCI
3 Carcinogens: Tobacco cessation and cancer risk Current Drinker Quit <10yrs yrs 20-29yrs >29yrs Never smoker Lung Ca. Peto, et al. BMJ Inherited factors Susceptibility to carcinogens modified by many factors First degree family members w/ 2-14 fold increase HNSCC risk related to tobacco use Non-smokers who get head and neck cancer Issues of second hand smoke Absorption of pro-carcinogen Tobacco exposure Activation to carcinogen Cytochrome p450 (CYP1- Detoxification GSTM1 Genetic syndromes associate with HNSCC HNSCC incidence FA /non-fa population Syndrome Gene Other cancers H & N Cancer Fanconi FANC family Hematological >500 fold higher rate N/A p16 Melanoma, pancreas Rare N/A RNASEL Prostate, cervix, breast 1.5 fold increased risk Bloom Xeroderma pigmentosum Helicase XP-A to XP-G UV induced skin cancer Rare Ataxia telangiectasia ATM Leukemia, lymphoma Rare Li Fraumeni p53 Lymphoma, sarcoma Race Cumulative Incidence % incidence by age Time to Squamous Cell Carcinoma (in years) 3
4 Rising prevalence of HPV+ oropharyngeal cancer Ω Colorado Sweden Michigan RTOG Ernster et al, Laryngoscope 2007 Nasman et al, Int J Cancer 2009 Maxwell et al, ClinCancer Res 2010 Ang et al, NEJM 2010 HPV associated cancer distribution Distribution of HPV types in HNSCC Oral Oropharynx Increased prevalence in oropharynx Kreimer. Cancer Epidemiol Biomarkers Prev
5 Implications of HPV on HNSCC Survival in HPV-HNSCC E6 p53 mutation p53 inactivation p16 Rb inactivation inactivation Rb inactivation E7 Gillison. JNCI 2000 Clinical trials analyses HPV + HPV- Tax % 31% ECOG % 62% RTOG % 57% RTOG % Impact of HPV in HNSCC Meta analysis-- 26% of HNSCC with HPV >40-8 of oropharyngeal cancers (exp. tonsil cancers) Related to sexual history Predilection for non-smokers Basaloid histology Improved outcome Gillison. JNCI 2000 Weinberg. JCO 2006 Kutler Singh JNCI
6 Genetic progression of head and neck cancer Barriers of targeted treatment in HNSCC Genomic instability 0 >10,000 mutations Normal mucosa Benign hyperplasia or alternate precursor 9p (p16) 3p, 17p (p53) Dysplasia 11q (Cyclin D1) 13q (Rb) 14q (?) Carcinoma in situ Invasive Cancer 6p 8 4q Cbioportal.org Bench to bedside- Immune modulation Response to anti-pd1 treatment Courtesy of Jose Baselga 6
7 Overcoming genetic complexity Biological parameters Chemoresponse (Singh et al. Head Neck 2002) HPV status (Gillison et al. JNCI 2000; Kutler Singh 2004) Genetic parameters Chromosomal profile Bockmul et al. AJP 2000 Wreesmann Singh. JCO 2004 Gene array Belbin, Singh, et al. Cancer Res 2002 Chung et al. Cancer Cell 2004 Gene panels Current application of genetic information Tumor suppressor genes p53 Phase III trial (INGN 201) Ad5CMV-p53 Phase III trial (INGN-T302) (+ Chemo) Oncogenes EGFR Bonner et al. N Engl J Med (+Rtx) Vermorken. EXTREME study. ASCO (+Chemo) RTOG-0522 (+ Rtx-Chemo) Other agents Phase III Iressa (ZD1839IL/0704) Traceva (ML20294) zalutumumab (Hx-EGFr-202; DAHANCA 19) panitumumab (SPECTRUM) VEGF and others Study of cancer genetics Targeting consequential mutations EGFR mutation lung cancer No mutations in 54 HNSCC primary tumors and cell lines 5 1 Responsive (n=10) Non-responsive (n=8) Negative Positive Pao...Singh, et al. PNAS Pham Singh. JCO 7
8 SCCRO in cancer Acticated in many different cancer types Common in for squamous cell carcinomas (lung, head and neck, cervix) occurring in >5 of cases Correlated with aggressive behavior Functions by controlling ubiqutination Singh B, et al. Cancer Res 2001 Singh B, et al. BMC Genetics 2002 Singh B, et al. Am J Pathol 2002 Singh B, et al. Genes Dev 2002\ Kim A. JBC 2009 Brodrick S, Neoplasia 2009 Huang G, JBC 2011 Results from CGAP for HNSCC Genotype SCCRO unmasks cancer activity RCAS vector injected No. Mice No. Tumors (%) Ntv-a wt SCCRO Ntv-a wt: RCAS-SCCRO Ntv-a Ink4a/Arf -/- : RCAS-SCCRO Ntv-a SCCRO Ink4a/Arf -/- Ntv-a Ink4a/Arf -/- loxp PTEN loxp SCCRO + Cre Recombinase Ntv-a Ink4a/Arf -/-, loxp PTEN loxp : RCAS-SCCRO, RCAS-Cre Ntv-a Ink4a/Arf - /- loxp PTEN loxp Cre Recombinase Ntv-a Ink4a/Arf -/- RCAS Ntv-a Ink4a/Arf -/- : RCAS-SCCRO Ntv-a Ink4a/Arf -/-, loxp PTEN loxp : RCAS-SCCRO, RCAS-Cre 8
9 SCCRO has matrix effects Rational for targeting SCCRO cm K O Wild Ubiquitin/Proteasome From bench to bedside: The story of SCCRO Determine cellular activity Highthroughput drug screening The Future 3 Singh B, et al. Cancer Res 2001 Singh B, et al. BMC Genetics 2002 Singh B, et al. Am J Pathol 2002 Singh B, et al. Genes Develop 2002 Determine onco-genic activity Huang G, et al. JBC 2011 Huang G, et al. JBC 2014 (in press) Fu W, et al. JBC (in revision) Huang Et al. Nature Cell Bio (submitted) Determine biochemical activity Completed lead compounds identified Improved understanding of HNSCC biology Improved utilization of biological data for diagnosis, prognosis and treatment Cloning/ Sequencing to identify SCCRO Ocharoenrat et al. ClinCanRes Sarkaria et al. Cancer Res Estillo, et al ClinCancerRes Brodrick et al., Neoplasia 2009 Wreesman et al, JCO 2011 Kim A et al, JBC 2008 Huang G, et al. JBC 2011 Huang et al. al. JBC 2014 (in press) Improved cure Singh B, et al. Genes Dev 2002 Sarkaria I, et al. Cancer Res
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