Tailoring Cancer Therapy in the Molecular Age Nancy E. Davidson, - - PowerPoint PPT Presentation

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Tailoring Cancer Therapy in the Molecular Age Nancy E. Davidson, - - PowerPoint PPT Presentation

Mar 10, 2024 335 likes •743 views

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

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Tailoring Cancer Therapy in the Molecular Age

Nancy E. Davidson, M.D.

Director, University of Pittsburgh Cancer Institute and UPMC Cancer Centers

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“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 this goal.”

Richard Nixon, State of the Union, January 22, 1971 President Nixon signing the National Cancer Act on December 23, 1971

40th Anniversary of the War on Cancer

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Tenth Anniversary of the Human Genome

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Declining Cancer Incidence

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Declining Cancer Mortality

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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

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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
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HMGB1 is Essential for Mitochondrial Quality Control

Tang et al Cell Metabolism, 2011

Lotze Van Houten Zeh

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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

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Genes that Regulate Squamous Differentiation Were Commonly Mutated

Stransky et al, Science, 2011

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HNSCC & BaF3 Functional Screening Platforms for “Driver Mutations” and Large Scale Drug Screen

“Driver” Mutation Functional Screen (survival/proliferation)

Top 40-50 & Mutations within same gene family/pathway

Large Scale Drug Screen

HNSCC (PCI-52) & BaF3 Platforms

Survival factor (FBS or IL-3)

+ driver mutation

(w/o FBS or IL-3) HNSCC cells/ BaF3

Stable HNSCC lines

  • r BaF3

HCS with small molecule libraries (10K-220K cpds)

High sensitivity correlated with particular mutation

HNSCC Mutation (vs wildtype)

Mutated gene

Lentivirus/ retrovirus production Survival factor withdrawal (w/o FBS, IL3) Cell Viability Screening (e.g. MTT) SCCHN (PCI-52) Or BaF3 Stable or transient

+/- Drug Screen

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  • 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

Total of 1356 compounds

I. High-throughput pre-clinical screening

  • LOPAC
  • NCI Approved oncology drug set II

II. Rational screening design: Survivin targeting (based on MCV studies)

Merkel Cell Polyomavirus: HTS and Rational Drug Screening

Moore, Chang, Kirkwood

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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
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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

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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

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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
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Development of MUC1 Vaccines for Cancer Prevention

Colon cancer Colonic polyp

Basic and preclinical studies

MUC1 is abnormally expressed on colon cancer and on premalignant polyps. MUC1 vaccine prevents spontaneous colitis-associated colon cancer in mice.

MUC1 Peptide – Poly-ICLC Adjuvant Vaccine for Prevention of Colon Cancer in Humans

Finn Schoen

Beatty et al, Cancer Prev Res, 2010

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Chemoprevention by NSAIDs

Zhang et al, PNAS 2010

Nonsteroidal anti- inflammatory drugs (NSAIDs) eliminate

  • ncogenic intestinal stem

cells via SMAC-dependent apoptosis

Yu Schoen Zhang

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Dietary phenethylisothiocyanate (PEITC), a component of cruciferous vegetables, suppresses prostate cancer progression in TRAMP mice

Powolny et al, JNCI 2011

Singh Normolle Beumer Nelson

Dietary PEITC Suppresses Prostate Cancer Progression

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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
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21

21

Adapted from Hudis. N Engl J Med. 2007;357:39.

Akt

SOS RAS RAF MEK

VEGF

MAPK

HER1, HER2, HER3, or HER4 HER2

Tyrosine kinase domains

PI3K

Cell proliferation Cell survival Cell mobility and invasiveness Cytoplasm Nucleus Transcription

X

Plasma membrane

HSP90

X X X

P P P P

Trastuzumab (Herceptin) Lapatinib (Tykerb) Tanespimyci n Pertuzumab Neratinib T-DM1

Strategies for Targeting HER-2

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Adjuvant Trastuzumab Therapy--N9831 and B-31

Perez et al, J Clin Oncol, 2011

  • Improved EFS

and overall survival

  • No clear

markers of response or resistance

  • Acceptable

toxicity

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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

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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
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Phase II NSCLC trial:

Fulvestrant and anastrozole, consolidation therapy, open for enrollment

Estrogen Signaling in Lung Cancer

Placenta NSCLC

Aromatase in Lung Tumors Pro-Growth Non-Genomic Signaling

Clin Cancer Res, 2011; J Steroid Biochem, 2009; JCO, 2006

SPORE in Lung Cancer V Foundation sponsored IIT

Stabile Dacic Tarhini Hershberger Siegfried

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Synthetic Lethality in BRCA Mutant Cancers

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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

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Single Agent ABT-888

Carboplati n and Paclitaxel

Gemcitabin e

Gemcitabine and Cisplatin Organ Dysfunction Study

Metronomic cytoxan

Phase I Trials of ABT 888 at UPCI

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Clinical Activity of Glioma Vaccines

Poly-ICLC-boosted αDC1-based glioma vaccines are safe, immunogenic, and clinically active

Okada et al., J Clin Oncol 2011

Kalinski Okada Bartlett Whiteside Butterfield Potter Pollack Mintz Zeh Hamilton Lieberman

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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
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Neurobiology of Chemotherapy- induced Nausea and Vomiting

Horn CC, et al, Am J Physiol, 2009 Horn CC et al, J Neurosci Methods, 2011

Musk shrew – A model for studying the biological controls of symptom clusters in cancer treatment Fos Expression

Horn

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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 uralensis Paeonia lactiflora Ziziphus jujube

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  • 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
  • Inhibition of angiogenesis and vascular permeability

PHY-906: Pre-Clinical Mechanisms of Action

Chu

Lam et al, Sci Trans Med, 2010

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Use of Modern Pharmacological Methods to Credential a Traditional Medicine

  • Multiple methods were used for quality control

and standardization, including chemical and biologic fingerprinting analyses.

  • In vivo mouse models show that PHY906

significantly reduces Irinotecan associated toxicity.

  • In vivo antitumor activity of Irinotecan is not

reduced by co-administration of PHY906.

  • These findings provide rationale for extending

these studies into the clinical setting.

  • Phase I trial of PHY906 and Irinotecan

successful completed.

Lam et al, Sci Transl Med, 2010 Kumman et al, Clin Colorectal Cancer, 2011

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Irinotecan + Placebo Irinotecan + PHY906

Failure of Oxaliplatin- Based Therapy (2nd-line mCRC)

Planned Randomized Phase II Study of

PHY906 + Irinotecan

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Pharmacogenome

Metabolome Proteome Transcriptome Epigenome Genome

The Power of Science in Personalized Cancer Medicine

Patient

Tumor

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  • Smart clinical trial design
  • Need for serial biological

samples

  • Adequate resources
  • Overcoming bureaucracy
  • Scientific literacy

Challenges for the Molecular Cancer Medicine

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  • Give the right treatment to the

right person at the right time

  • Goals

–Maximize efficacy –Minimize side effects –Minimize cost

Personalized Cancer Medicine

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Bridging Laboratory to Clinic to Community University of Pittsburgh Cancer Institute Patient-Centered and Research-Driven