Transcript Cancer Risk Factors

Personalized Cancer Medicine – Winning
the War on Cancer
Zhiyong Li, MD, PhD.
Dallas Cancer Specialists
315 N. Shiloh Road, Suite 101
Garland, Texas 75042
972-487-8866
Personalized Cancer Medicine
•
•
•
•
Cancer Burden
Resource for fighting war on cancer
Achievements
Future of cancer medicine
Global Cancer Burden in 2012
• All sites
• Breast
New cases
Cancer deaths
14.1 million
1.7 million
8.2 million
522, 000
3
Estimated US Cancer Statistics, 2013
• All Sites
• Breast
New Cases
1,660,290
234,580
Deaths
580,350
40,030
Bills for Cancer Research
1. The National Cancer Act - Enacted December 23, 1971
2. National Cancer Amendments - Enacted July 23, 1974
3. Biomedical Research and Research Training Amendments - Enacted
November 9, 1978
4. Health Research Extension Act - Enacted November 20, 1985
5. Health Omnibus Program Extension - Enacted November 4, 1988
6. National Institutes of Health Reform – Enacted January 15, 2007
Resource spent for cancer
research & treatment
•NCI has spent some $90 billion
•Some 260 nonprofit organizations in US have dedicated
themselves to cancer (more than the number established for
heart disease, AIDS, Alzheimer’s disease, and stroke
combined).
•These 260 organizations spent > $2.2 billion annually
•The United States has spent > a trillion dollars for war on
cancer
Signal transduction pathways
Cancer – a Disease of Genome
• Cancer is a disease characterized by the
uncontrolled growth of abnormal cells in the body.
• Cell growth is regulated by genes encoded in the
DNA molecules of the chromosomes.
• Mutations in those genes overstimulate cell
growth, keeping the cell active when it should be
at rest.
The Human Genome Project
• Began in 1990, and completed in 2003
• The full sequence was completed and
published in April 2003.
The Cancer Genome Atlas (TCGA)
• Cancer: errors in DNA
uncontrolled growth.
• Identifying the changes in each cancer’s genome
• Understanding how such changes drive the disease
• Providing the foundation for improving cancer
prevention, early detection and treatment.
The Cancer Genome Atlas (TCGA)
• 2006 - TCGA began as a three-year pilot
• National Cancer Institute and National Human Genome
Research Institute committed $100 million
• 2008 - TCGA reported first result: GBM
• 2009 - began to map 20 cancers.
• 2011 - 5,000th case ships to TCGA centers
Her2 pathway
Her2 pathway
• HER2 overexpression: 20% patients with breast cancer
• Drugs that target the Her2 protein
– Herceptin (Trastuzumab): McAb
– Kadcyla (TDM-1): an Ab-drug conjugate, Herceptin attached to a
chemo drug DM-1.
– Perjeta (Pertuzumab ): McAb
– Tykerb (Lapatinib): an oral drug that targets the Her2 protein.
PI3K/Akt/mTOR pathway
Growth factor
receptor
PI3K/Akt/mTOR pathway
• the most frequently dysregulated in cancer.
• Implicated in oncogenesis, progression, and
resistance to conventional anticancer therapies.
• Inhibition of this pathway has been shown to halt
tumor growth, leading to tumor regression.
• PI3K inhibitors showed synergistic activity with
cytotoxic and targeted agents, and have restored
sensitivity to these drugs
•
PI3K/Akt/mTOR pathway
•
•
•
•
•
•
•
•
•
Afinitor: approved for RCC and ER+ BC
Torisel: approved for RCC
Buparlisib (BKM120): an oral pan-PI3K inhibitor.
BYL719 : PI3K a inhibitor
XL147: a selective PI3K inhibitor,
XL765: a dual mTOR and PI3K inhibitor
Idelalisib: PI3K d inhibitor, ? approval for CLL
Pictilisib (GDC-0941): PI3K a/d inhibitor
IPI – 145: PI3K d/g inhibitor
Cyclin-Dependent Kinase 4 and 6
(CDK4/6) Pathway
• Palbociclib - "breakthrough therapy" designated by
FDA in 2013.
• The phase II PALOMA-2 trial:
• The phase III PALOMA-3 trial:
• LEE011: the most selective CDK4/6 inhibitor
• LY2835219: CDK4/6 inhibitor
The Ras/Raf/MEK/ERK pathway
The Ras/Raf/MEK/ERK pathway
• Vemurafenib, BRAF inhibitor, Melanoma
• Dabrafenib, BRAF inhibitor, Melanoma
• Trametinib, BRAF inhibitor, Melanoma
• Dinaciclib
• Lonafarnib and tipifarnib
• Salirasib
• Deltarasin
EGFR pathway
• Tyrosine Kinase Inhibitors (TKIs)
• 1st generation:
Iressa (gefitinib)
Tarceva (Erlotinib)
2nd generation:
Gilotrif (Afatinib)
Neratinib
Dacomitinib
• 3rd generation:
CO-1686
AZ9291
WZ-4002
HM61713
EGFR pathway
• Monoclonal Antibody:
Cetuximab (Erbitux)
Vectibix (Panitumumab)
Zalutumumab
Nimotuzumab
Matuzumab
ALK/ROS1 pathway
• Xalkori (Crizotinib)
• Zykadia (Ceritinib), approved on 5/1/2014
• CH5424802
• AP26113
Foundation Medicine, Inc.
• The company offers FoundationOne, a
molecular information product for the
analysis of routine cancer specimens,
enabling physicians to provide targeted
oncology therapies and optimize treatments.
Actionable Mutations in TNB
• Poor prognosis: WNK1, TP53, JAK1, DCHS2, ITSN2,
ADH8A1
• Favorable prognosis: ATXN7, MST1,HGF, PLXNA3,
CSDE1
•
•
•
•
•
TP53: vaccine, gene therapy, WEE-1 inhibitor, Kevetrin
PARP: PARP inhibitors
ESR: alternative endocrine therapy
JAK1: JAK1 inhibitors
mTOR: mTOR inhibitors
VEGF pathway
• Avastin: a McAb targets VEGF.
• Zaltrap: a fusion protein inhibits VEGF
• VEGFR Tyrosine Kinase Inhibitors (TKIs)
– Sutent (Sunitinib)
– Votrient (Pazopanib)
– Nexevar (Sorafenib)
– Inlyta (Axitinib)
HDAC inhibitors
• Histone deacetylase involves controlling
gene expression
• Histone deacetylase inhibitors (HDAC
inhibitors): inhibit histone deacetylase, and
thereby affecting gene expression.
• Entinostat : “Breakthrough Therapy”
designation for advanced breast cancer
Cancer Immunotherapy
• Provenge (sipuleucel-T)
Approved in April 29, 2010
A dendritic cell vaccine for mCRPC
Cancer Immunotherapy
• Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)
inhibitor
– Functioning as a brake on T cells,
– Preventing T cells from launching full-out immune
attacks.
Blocking the CTLA-4 molecule would set T cells
free to destroy cancer.
– In 2011, the U.S. FDA approved anti–CTLA-4
treatment, Yervoy (ipilimumab, BMS), for metastatic
melanoma.
Cancer Immunotherapy
• Programmed Death 1 (PD-1) inhibitor
– another brake on T cells.
• Blocking PD-1 by an anti–PD-1 antibody
would set T cells free to destroy cancer.
–
–
–
–
Nivolumab (Bristol-Myers Squibb)
MK-3475 (Merck & Co)
MPDL3280A (Roche's Genentech)
MEDI 4736 (AztraZeneca)
Cancer Immunotherapy
• Chimeric Antigen Receptor therapy
(CAR therapy)
– A personalized treatment involves genetically
modifying a patient's T cells to make them
target tumor cells.
– Highly effective in leukemia and lymphoma.
Nanothechnology
• Nanoparticles in treatment of cancer
– As carrier to targeted delivery of drug to
cancer site
• Nanoparticles in diagnosis of cancer
– Early detection of cancer
– Monitoring the cancer response to treatment
Successful Story
• Chronic Myeloid Leukemia (CML)
– Most fatal disease, median survival ~ 3 years.
– Prior to 2001, only treatment:
• Chemotherapy
• Interferon
• BMT
Successful Story
• Chronic Myeloid Leukemia (CML)
–
–
–
–
–
Gleevec was 1st TKI approved in 2001
The most effective with minimal side effect.
Targeted therapy for BCR/ABL gene rearrangement
Now median survival for CML – projected 30 years.
New 2nd and 3rd generation
•
•
•
•
•
Tasigna
Sprycel
Bosutinib
Ponatinib (Iclusig)
Omacetaxine (Synribo).
Chronic Lymphocytic Leukemia
• Median survival: 15-20 years
• Ibrutinib is 1st BTK inhibitor approved
for CLL in Feb, 2014
• Idelalisib is PI3K inhibitor waiting for
approval for CLL
Chronic Lymphocytic Leukemia
• BTK inhibitors
–
–
–
–
Ibrutinib
CC-292
ONO-4059
ACP-196
• Syk inhibitors
– GS-9973
– Cerdulatinib
• PI3K inhibitors
–
–
–
–
–
–
Idelalisib
GS-9820
IPI-145
AMG 319
TGR-1202
SAR245408
• BCL2 inhibitors
– ABT - 199
– AT - 101
Personalized Cancer Medicine
Will Win the War on Cancer
Cancer Awareness Program
for Patient Advocate & Public Education
Dallas Cancer Specialists
315 N. Shiloh Road, Suite 101
Garland, Texas 75042
972-487-8866