Dallas Cancer Specialists 315 N. Shiloh Road, Suite 101 Garland, Texas Zhiyong Li, MD, PhD. Personalized Cancer Medicine – Winning the War on Cancer

Personalized Cancer Medicine Cancer Burden Resource for fighting war on cancer Achievements Future of cancer medicine

3 Global Cancer Burden in 2012 New cases Cancer deaths All sites14.1 million 8.2 million Breast1.7 million522, 000

Estimated US Cancer Statistics, 2013 New Cases Deaths All Sites 1,660, ,350 Breast 234,580 40,030

Bills for Cancer Research 1. The National Cancer Act - Enacted December 23, National Cancer Amendments - Enacted July 23, Biomedical Research and Research Training Amendments - Enacted November 9, Health Research Extension Act - Enacted November 20, Health Omnibus Program Extension - Enacted November 4, 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) TCGA began as a three-year pilot National Cancer Institute and National Human Genome Research Institute committed $100 million TCGA reported first result: GBM began to map 20 cancers ,000 th case ships to TCGA centers

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. Her2 pathway

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

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  inhibitor, ? approval for CLL Pictilisib (GDC-0941): PI3K  inhibitor IPI – 145: PI3K  inhibitor PI3K/Akt/mTOR pathway

Cyclin-Dependent Kinase 4 and 6 (CDK4/6) Pathway Palbociclib - "breakthrough therapy" designated by FDA in The phase II PALOMA-2 trial: The phase III PALOMA-3 trial: LEE011: the most selective CDK4/6 inhibitor LY : CDK4/6 inhibitor

The Ras/Raf/MEK/ERK pathway

Vemurafenib, BRAF inhibitor, Melanoma Dabrafenib, BRAF inhibitor, Melanoma Trametinib, BRAF inhibitor, Melanoma Dinaciclib Lonafarnib and tipifarnib Salirasib Deltarasin The Ras/Raf/MEK/ERK pathway

EGFR pathway Tyrosine Kinase Inhibitors (TKIs) 1 st generation: Iressa (gefitinib)Iressa (gefitinib) Tarceva (Erlotinib) 2 nd generation: Gilotrif (Afatinib) Neratinib Dacomitinib 3rd generation:CO-1686 AZ9291 WZ-4002 HM61713

Monoclonal Antibody: Cetuximab (Erbitux) Vectibix (Panitumumab) Zalutumumab Nimotuzumab Matuzumab EGFR pathway

ALK/ROS1 pathway Xalkori (Crizotinib) Zykadia (Ceritinib), approved on 5/1/2014 CH 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 expressionHistone deacetylase Histone deacetylase inhibitors (HDAC inhibitors): inhibit histone deacetylase, and thereby affecting gene expression.histone deacetylase Entinostat : “Breakthrough Therapy” designation for advanced breast cancer

Cancer Immunotherapy Provenge (sipuleucel-T) Approved in April 29, 2010 A dendritic cell vaccine for mCRPC

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. Cancer Immunotherapy

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 Nanothechnology

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 1 st 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 2 nd and 3 rd generation Tasigna Sprycel Bosutinib Ponatinib (Iclusig) Omacetaxine (Synribo). Successful Story

Median survival: years Ibrutinib is 1 st 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 Chronic Lymphocytic Leukemia PI3K inhibitors –Idelalisib –GS-9820 –IPI-145 –AMG 319 –TGR-1202 –SAR BCL2 inhibitors –ABT –AT - 101

Personalized Cancer Medicine Will Win the War on Cancer

Dallas Cancer Specialists Cancer Awareness Program for Public for Patient Advocate & Public Education 315 N. Shiloh Road, Suite 101 Garland, Texas