Cancer Biology: targeting therapy to maximize benefit and minimize side effects

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Cancer Biology targeting therapy to maximize
benefit and minimize side effects

• Ana María López, MD, MPH, FACP
• Professor of Medicine and Pathology
• Arizona Cancer Center
• University of Arizona

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Question 1

• What are VEGF, erbb2 and BCR-ABL?
• New punk rock bands
• Genetic mutations that mark the aggressiveness of
  cancer
• Tumor markers that relate to cell differentiation
• Molecular targets for cancer therapy

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Question 1

• What are VEGF, erbb2 and BCR-ABL?
• New punk rock bands
• Genetic mutations that mark the aggressiveness of
  cancer
• Tumor markers that relate to cell differentiation
• Molecular targets for cancer therapy

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Ripped from the Headlines
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(Sciencedaily.com- (http//www.sciencedaily.com/i
mages/2008/11/081125113114-large.jpg))
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Learning Objectives

• 1. To delineate the role of cancer biology in the
  diagnosis and prognosis of cancer patients.
• 2. To provide 3 examples of the role of cancer
  biology in cancer management.

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Pharmacologic Methods for Preventing Abnormal
Cell Division
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Breast Cancer ? Breast Cancer
?
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Carcinogenesis Hallmarks of Cancer
(Cancer Biology Genetics I- Carcinogenesis /
Margaret M. Briehl, Ph.D.)
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Genetics Alterations The Hallmarks of Cancer
Self-Sufficiency in Growth Signals
Insensitivity to Anti-Growth Signals
Invasion Metastasis
Loss of Rb
Ras mutations
? Bcl-2
? c-myc
BCR-ABL
? VEGF
P53 mutation
? Her-2 neu
Sustained Angiogenesis
Evading Apoptosis
Limitless Replicative Potential
? Her-2 neu
? TGFß
? Her-2 neu
P53 mutation
(Cancer Biology Genetics II- Hallmarks /
Margaret M. Briehl, Ph.D.)
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Carcinogenesis The Vogelgram
(Cancer Biology Genetics I- Carcinogenesis /
Margaret M. Briehl, Ph.D.)
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Personalized Medicine in Cancer
(Cancer Biology Genetics I- Personalized
Medicine/ Margaret M. Briehl, Ph. D.)
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Vision for the Transformation of Medicine in the
21st Century
Participatory
(Cancer Biology Genetics I- Transformation in
Medicine/ Margaret M. Briehl, Ph. D.)
I predict that comprehensive, genomics-based
health care will become the norm with
individualized preventive medicine and early
detection of illnesses. - Elias A. Zerhouni,
2006
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Vocabulary

• Gene expression profiling
• discovery of patterns to predict treatment
  response
• Proteomics
• identify serum markers to monitor treatment
  response
• Pharmacogenomics
• use genetic information to optimize treatment
  dose

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Gene Chip Technology
(Cancer Biology Genetics I-Gene Chip
Technology/ Margaret M. Briehl, Ph.D.)
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Proteomics

• Goals
• Identify biomarkers of early disease
• Monitor response to therapy
• Predict likelihood of relapse after therapy

http//www.scq.ubc.ca/wp-content/uploads/2006/08/P
roteomics.gif
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Pharmacogenomics
Drug Interactions
Environmental Factors
Variations in drug response

• Study of inherited differences in drug
  disposition and effects
• Largely focused on genetic polymorphisms in drug
  metabolizing enzymes

Genetic Factors
Cell
Transport
Anticancer drugs
(Cancer Biology Genetics I- Pharmacogenomics /
Margaret M. Briehl, Ph.D.)
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Examples of Targeted Therapy

• Melanoma
• Breast cancer
• GIST
• Stomach cancer

• Hematological cancer
• Prostate cancer
• Thyroid cancer

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Melanoma
www.microvet.arizona.edu/.../CaseMelanoma.htm
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Melanoma

• Incidence of melanoma in the US is increasing
• faster than other cancers
• 1940 1 in 1500
• 2004 1in 67
• 2010 1 in 50
• Most common cancer in 20s
• 2009
• 68,720 diagnosed
• 8650 deaths
• Most do not respond to chemotherapy

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Predicting Melanoma

• 8 genes predict who will respond to treatment
• 21 pts with metastatic melanoma some responded
  to chemo, some did not
• Mathematical analysis of 25,000 genes to identify
  responders and nonresponders
• Being validated in larger n
• genes found may be potential targets for new
  therapies

biotech-weblog.com
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Vaccine for advanced melanoma

• Phase III trial vaccine/IL2 vs IL2
• N185
• Vaccine 22.1 response rate vs 9.7 response rate
• Progression free survival 2.9 months vs 1.6
  months
• Overall survival 17.6 months vs 12.8 months

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Breast Cancer
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Breast cancer

• BRCA 1/2 testing commercially available
• Identifies a tumor suppressor gene mutation
• Increased risk breast, ovarian, pancreatic, colon
  and prostate cancers
• Testing identifies target for surgical and/or
  chemo-prevention

cmbi.bjmu.edu.cn/.../200291321.jpg
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Oncotype DX gene signature predicts response to
chemotherapy
http//www.oncotypedx.com/Images/HCP/ClinicalValid
ation.gif
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ERB B2

• Gene encoding epidermal growth factor receptor-2
• Also called Her2-neu
• Gene amplification is seen in 25 of breast
  cancers

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ERB B2 and Breast Cancer
ERB B2
?
Self-Sufficiency in Growth Signals
(Cancer Biology Genetics II- ERB-B2 / Margaret
M. Briehl, Ph.D.)
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ERB B2 and Breast Cancer
12.5 kb
Southern
4.4 kb
Northern
p185
Western
IHC
Slamon et al. Science 244707, 1989
(Cancer Biology Genetics II- ERB-B2 / Margaret
M. Briehl, Ph.D.)
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ERB B2 and Breast Cancer
Menard et al. Oncology 6(suppl 2)67, 2001
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ERB B2 Breast Cancers More Aggressive
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ERB B2 and Breast Cancer

• Shorter relapse times

• Faster tumor growth rate
• Poor response to chemotherapy

Menard et al. Oncology 6(suppl 2)67, 2001
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Her-2/neu

• 20 to 30 of breast cancers
• Adverse prognostic sign
• Trastuzumab
• targets Her-2
• attached to HER2 protein so the chemical signals
  that stimulate tumor growth are blocked
• reduces recurrence by about 50

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Treatment of Breast Cancer with Trastuzumab
Slamon et al. N Engl J Med 344783, 2001
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Treatment of Breast Cancer with Trastuzumab
Slamon et al. N Engl J Med 344783, 2001
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Addition of Trastuzumab To Other Therapies
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Testing for ERB B2 Overexpression
(Cancer Biology Genetics II- ERB-B2 / Margaret
M. Briehl, Ph.D.)
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Her-2/neu

• Lapatinib 2nd line therapy, trastuzumab
  resistant
• With chemotherapy capecitabine

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Phase II study T-MDI

• T-MDI is a new class of drug known as
  antibody-drug conjugates
• monoclonal antibodies linked with cytotoxic
  agents
• trastuzumab delivers DMI directly to the tumor,
  targets the cancer cell, maximizes clinical
  benefit and minimizes side effects
• N112
• 35 tumor shrinkage or disease stabilization for
  6 months after receiving T-DMI
• Phase III study comparing T-DMI with
  lapatinib/capecitabine

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http//www.biooncology.com/bioonc/research/her/adc
/index.m
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Triple negative disease

• Difficult to treat
• Poorer survival
• 15 breast cancers
• Express enzyme PARP1- Poly (ADP-ribose)
  polymerase, member 1
• Target to increase response to chemo

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BSI-201

• Phase II clinical trial
• Metastatic breast cancer
• Gemcitabine/carbo/PARP1 vs Gemcitabine/carbo
• OR 48 vs 16
• Median survival 9.2 vs 5.7m
• PFS 6.9 vs 3.3 months
• Side effects similar
• New class of cancer drug showed
• significant benefits in cancer patients.

http//en.wikipedia.org/wiki/PARP1
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GIST
liferaftgroup.org
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Gastrointestinal stromal tumors (GIST)

• Formerly incurable
• Found to express c-kit
• Imatinib targets c-kit
• 80 of patients demonstrate a response
• 20 expression of 38 genes
• Of which, 20 KRAB-zinc finger genes
• Opportunity for new targeted therapy

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Gastrointestinal stromal tumors (GIST)
www.gistalliance.com/images/partial_responses
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Stomach Cancer
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Stomach Cancer

• 4th most common cancer in the world
• 2nd most common cause of cancer death in the
  world
• Her-2/neu expression
• More aggressive
• Poorer outcomes
• 22 stomach cancers

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Stomach Cancer ToGA trial

• Add trastuzumab to chemotherapy
• Better response with higher Her-2 expression
• Median survival reached 16 months in higher
  expressors vs 10 months without trastuzumab

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Question 2

• The 2 diagnoses for hematological malignancies
  are leukemia and lymphoma.
• 1. true
• 2. false

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Hematologic Cancers

• Leukemia and lymphoma are the histological
  diagnoses
• Cellular and genetic analysis reveals
• 38 types of leukemia
• 51 types of lymphoma
• Subtyping has improved survival for patients who
  can be treated based on subtype.

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Acute promyelocytic leukemia

• Translocation 1517
• all-trans retinoic acid (ATRA) induces maturation
  of the immature cell

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Chronic Myelogenous Leukemia
(Cancer Biology Genetics II- Myelogenous /
Margaret M. Briehl, Ph.D.)
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Chronic Myelogenous Leukemia
Ph
(Cancer Biology Genetics II- Myelogenous /
Margaret M. Briehl, Ph.D.)
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BCR-ABL in Chronic Myeloid Leukemia

• ABL is a non-receptor tyrosine kinase
• The t(922) in CML generates novel fusion
  proteins, designated BCR-ABL
• The fusion proteins have constitutive tyrosine
  kinase activity (i.e., normal regulation is lost)
• Imatinib mesylate was developed to target BCR-ABL

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Imatinib Mesylate in the Treatment of CML

• Its development was the start of molecularly
  targeted therapies for cancer
• Alternate names ST1571, imatinib mesylate and
  imatinib
• Recognizes the ATP binding site of ABL
• Inhibits the constitutive tyrosine kinase
  activity

(Cancer Biology Genetics II- Gleevec/ Margaret
M. Briehl, Ph.D.)
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Imatinib Mesylate - Phase III Clinical Trial
Results

• Newly diagnosed patients with chronic-phase CML
• Randomly assigned
• interferon alpha plus low dose cytarabine (553
  patients)
• imatinib (553 patients)
• 318 of the combination therapy patients
  eventually crossed over to imatinib

OBrien et al. N Engl J Med 348994, 2003
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Imatinib Mesylate - Phase III Clinical Trial
Results
OBrien et al. N Engl J Med 348994, 2003
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Diffuse Large B-Cell Lymphoma

• Most common type of aggressive lymphoma
• Standard therapy cures some of the DLBCL patients
• Remaining patients have a high probability of
  death within 5 years
• Clinical factors are somewhat predictive of
  treatment outcome
• Key Question What is the biology underlying the
  disparate treatment outcome?

(Cancer Biology Genetics I- Diffuse / Margaret
M. Briehl, Ph.D.)
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Gene Expression Profiling of DLBCL

• 240 patients with Diffuse Large B-cell Lymphoma
• Specimens collected at the time of diagnosis
• All patients received adriamycin-based
  chemotherapy
• Gene expression was compared to patient outcome

Alizadeh et al., Nature, 2000
(Cancer Biology Genetics I- Gene Expression /
Margaret M. Briehl, Ph.D.)
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Gene Expression Profiling DLBCL
1) Identified DLBCL subtypes 2) Subtypes reflect
the tumor biology 3) Subtypes add to the
predictive power of the clinical features
(Cancer Biology Genetics I- Gene Expression /
Margaret M. Briehl, Ph.D.)
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Lung Cancer
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Non-small Cell Lung CancerDouble-blind, Phase
III study

• N768
• maintenance therapy in patients with advanced
  NSCLCnew concept
• Erlotinib/bevacizumab vs bevacizumab
• erlotinib with bevacizumab slowed cancer growth
  more bevacizumab alone

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Non-small Cell Lung CancerPhase III Study

• N1390
• docetaxel plus vandetanib or docetaxel plus
  placebo.
• 21 reduction in disease progression
• median progression-free survival 17.3 vs. 14
  weeks in the control arm
• Adding a targeted therapy to a second-line
  benefited patients with NSCLC

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Prostate Cancer
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Prostate Cancer early onset

• Genetic marker predicts early onset of prostate
  cancer T allele of Met160Val
• Who white men with a FH of prostate cancer2-
  fold increased risk of developing prostate cancer
  and of developing it earlier
• Future directions
• confirm in a larger population
• examine in African Americans
• Implications identify who needs earlier
  screening

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Prostate cancer tissue hypoxia and disease
recurrence

• Hypoxia in tumors is a risk factor for radiation
  resistance
• 57 pts probe assessed oxygen level in prostate
  cancer tissue and normal healthy tissue prior to
  onset of XRT (nl 24xgtO2)
• Stratifying for other risk factors such as tumor
  grade, hypoxia emerged as an independent
  predictor of PSA increase and disease recurrence

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Thyroid Cancer
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Thyroid Cancer

• More common in women
• Incidence is increasing
• 2008 37,000 new cases and 1590 deaths
• Most patients do well good prognosis after
  surgery and treatment with radioiodine
• 5 experience rapidly progressing,
  life-threatening disease does not respond to
  conventional treatment

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Pazopanib

• 2nd generation multitargeted tyrosine kinase
  inhibitor against VEGF-R, platelet-derived
  growth factor and C-kit
• N37
• 66 PR

http//oncochat.typepad.com/.a/6a00d8342ae08153ef0
10534c74a76970c-800wi
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Sorafenib

• Inhibits blood vessel growth
• Median OS 140 wks (JCO 2008)
• Guidelines sorafenib for radioactive
  iodine-refractory thyroid cancer
• Ist significant progress since doxorubicin was
  approved in 1974 with a response in only 5 of pts

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Take-home Message

• Global cancer burden is increasing
• Expected to triple by 2030
• Advances in
• Pharmacogenetics, Nanotechonology, Biotechnology,
  Robotics
• Increased understanding of biology of cancer

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Questions?