Tailoring Cancer Therapy in the Molecular Age Nancy E. Davidson, M.D. Director, University of Pittsburgh Cancer Institute and UPMC Cancer Centers
40 th Anniversary of the War on Cancer “I will also ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve President Nixon signing the National this goal.” Cancer Act on December 23, 1971 Richard Nixon, State of the Union, January 22, 1971
Tenth Anniversary of the Human Genome
Declining Cancer Incidence
Declining Cancer Mortality
University of Pittsburgh Cancer Institute • 348 faculty members from 37 academic departments of University of Pittsburgh • Clinical research and care through UPMC hospitals and Cancer Centers
Goals of Molecular Cancer Medicine • Identify causes of cancer • Estimate risk of developing cancer • Detect cancer early • Prevent or delay cancer • Gauge prognosis at diagnosis • Predict response to therapy • Identify new targets for therapy • Provide supportive care
HMGB1 is Essential for Mitochondrial Quality Control Lotze Van Houten Zeh Tang et al Cell Metabolism, 2011
Mutational Landscape of HNSCC Whole exome sequencing of 92 tumors + bloods • Average of 130 (17- 731) mutations/tumor • Mutation rate of HPV+ < HPV- • Mutation rates similar to other smoking- related cancers Stransky et al, Science, 2011 Grandis
Genes that Regulate Squamous Differentiation Were Commonly Mutated Stransky et al, Science, 2011
HNSCC & BaF3 Functional Screening Platforms for “ Driver Mutations ” and Large Scale Drug Screen “ Driver ” Mutation Functional Screen HNSCC (survival/proliferation) Mutated Mutation gene (vs HNSCC (PCI-52) & BaF3 Platforms wildtype) + driver Survival factor mutation Lentivirus/ retrovirus (FBS or IL-3) (w/o FBS or HNSCC cells/ production IL-3) BaF3 Top 40-50 & Stable or Mutations transient SCCHN (PCI-52) within Or BaF3 same gene Survival factor family/pathway withdrawal (w/o FBS, IL3) +/- Drug Screen Cell Viability Screening Large Scale Drug Screen (e.g. MTT) HCS with High sensitivity small molecule correlated with libraries Stable particular mutation (10K-220K cpds) HNSCC lines or BaF3
Merkel Cell Polyomavirus: HTS and Rational Drug Screening I. High-throughput pre-clinical screening - LOPAC - NCI Approved oncology drug set II II. Rational screening design: Survivin targeting (based on MCV studies) Total of 1356 compounds • Bortezomib and YM155 <100 nM IC50 • Mouse xenograft studies • Approval of LOI for phase 2 trial of bortezomib from ECOG in March 2011 • Collaboration with Melanoma Program Moore, Chang, Kirkwood
Goals of Molecular Cancer Medicine • Identify causes of cancer • Estimate risk of developing cancer • Detect cancer early • Prevent or delay cancer • Gauge prognosis at diagnosis • Predict response to therapy • Identify new targets for therapy • Provide supportive care
Cancer Screening — A Moving Target • In 2011 – Refinement of guidelines for mammography and Paps smears for breast and cervical cancer – Concern about value of PSA for prostate cancer – New support for CAT scanning for lung cancer – Emphasis on colon cancer screening
Outcomes in the Pittsburgh Lung Cancer Screening Study 3,643 Smokers Enrolled in CAT Scan Screening Study • 2.2% diagnosed with lung cancer during first 3 years of follow-up (80 cases, 40 Stage I) • 1.0% had a CAT scan-screen-related major chest surgery showing a benign diagnosis • PET imaging had poor positive predictive value • Ongoing proteomic and genetic studies for biomarkers to improve risk prediction Wilson Seigfried Weissfeld
Goals of Molecular Cancer Medicine • Identify causes of cancer • Estimate risk of developing cancer • Detect cancer early • Prevent or delay cancer • Gauge prognosis at diagnosis • Predict response to therapy • Identify new targets for therapy • Provide supportive care
Development of MUC1 Vaccines for Cancer Prevention Basic and preclinical studies Colonic polyp Colon cancer MUC1 is abnormally expressed on colon cancer and on premalignant MUC1 vaccine prevents polyps. spontaneous colitis-associated colon cancer in mice. Schoen Finn MUC1 Peptide – Poly-ICLC Adjuvant Vaccine for Prevention of Colon Cancer in Humans Beatty et al, Cancer Prev Res, 2010
Chemoprevention by NSAIDs Nonsteroidal anti- inflammatory drugs (NSAIDs) eliminate oncogenic intestinal stem cells via SMAC-dependent apoptosis Zhang et al, PNAS 2010 Zhang Yu Schoen
Dietary PEITC Suppresses Prostate Cancer Progression Beumer Singh Normolle Nelson Dietary phenethylisothiocyanate (PEITC), a component of cruciferous vegetables, suppresses prostate cancer progression in TRAMP mice Powolny et al, JNCI 2011
Goals of Molecular Cancer Medicine • Identify causes of cancer • Estimate risk of developing cancer • Detect cancer early • Prevent or delay cancer • Gauge prognosis at diagnosis • Predict response to therapy • Identify new targets for therapy • Provide supportive care
Strategies for Targeting HER-2 Trastuzumab Pertuzumab T-DM1 (Herceptin) HER2 HER1, HER2, HER3, or HER4 VEGF X X HSP90 P PI3K Tanespimyci SOS Plasma P membrane Tyrosine kinase n X domains Neratinib X P RAS Akt Lapatinib RAF P MAPK (Tykerb) MEK Cytoplasm Cell proliferation Cell survival Cell mobility and invasiveness Nucleus Transcription 21 Adapted from Hudis. N Engl J Med. 2007;357:39. 21
Adjuvant Trastuzumab Therapy--N9831 and B-31 • Improved EFS and overall survival • No clear markers of response or resistance • Acceptable toxicity Perez et al, J Clin Oncol, 2011
Importance of Predictive Assay • Possible assays for HER-2 • IHC • FISH • RT-PCR (Oncotype) • Two examples of discordant assays — HER-2 and FISH- positive but RT-PCR - negative Dabbs et al, J Clin Oncol, 2011
Goals of Molecular Cancer Medicine • Identify causes of cancer • Estimate risk of developing cancer • Detect cancer early • Prevent or delay cancer • Gauge prognosis at diagnosis • Predict response to therapy • Identify new targets for therapy • Provide supportive care
Estrogen Signaling in Lung Cancer SPORE in Lung Cancer V Foundation sponsored IIT Pro-Growth Non-Genomic Aromatase in Lung Tumors Signaling Placenta NSCLC Clin Cancer Res, 2011; J Steroid Biochem, 2009; JCO, 2006 Phase II NSCLC trial: Fulvestrant and anastrozole, consolidation therapy, open for enrollment Stabile Dacic Hershberger Siegfried Tarhini
Synthetic Lethality in BRCA Mutant Cancers
Synthetic Lethality in BRCA Mutant Cancers Hypothesis PARP inhibitors are active against BRCA mutant cancers Hypothesis PARP inhibitors can potentiate DNA damaging effects of chemotherapy
Phase I Trials of ABT 888 at UPCI Carboplati n and Paclitaxel Metronomic Gemcitabin cytoxan e Single Agent ABT-888 Organ Gemcitabine Dysfunction and Cisplatin Study
Clinical Activity of Glioma Vaccines Poly-ICLC- boosted αDC1 -based glioma vaccines are safe, immunogenic, and clinically active Whiteside Butterfield Okada Kalinski Potter Hamilton Mintz Bartlett Pollack Lieberman Zeh Okada et al., J Clin Oncol 2011
Goals of Molecular Cancer Medicine • Identify causes of cancer • Estimate risk of developing cancer • Detect cancer early • Prevent or delay cancer • Gauge prognosis at diagnosis • Predict response to therapy • Identify new targets for therapy • Provide supportive care
Neurobiology of Chemotherapy- induced Nausea and Vomiting Musk shrew – A model for studying the biological controls of symptom clusters in Horn cancer treatment Fos Expression Horn CC, et al, Am J Physiol, 2009 Horn CC et al, J Neurosci Methods, 2011
The Example of PHY906 • Traditional Chinese botanical formulation composed of four main herbs – Huang Qin Tang (HQT) • Used in Asia for a variety of gastrointestinal ailments since 300 AD Scutellaria baicalensis Glycyrrhiza Paeonia lactiflora Ziziphus jujube uralensis
PHY-906: Pre-Clinical Mechanisms of Action • Inhibition of NF- B activity – Enhances chemosensitivity – Reverses drug resistance • Inhibition of inflammatory cytokines and chemokines – TNF- α – IFN- γ – MCP-1 • Inhibition of invasion/metastasis – MMP2 > MMP-3 > MMP-9 • Inhibition of MDR Chu • Inhibition of angiogenesis and vascular permeability Lam et al, Sci Trans Med, 2010
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