Personalized Cancer Medicine Winning the War on Cancer

Personalized Cancer Medicine – Winning the War on Cancer Zhiyong Li, MD, Ph. D. 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 14. 1 million 1. 7 million Cancer deaths 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, 000 th case ships to TCGA centers

Her 2 pathway

Her 2 pathway • HER 2 overexpression: 20% patients with breast cancer • Drugs that target the Her 2 protein – Herceptin (Trastuzumab): Mc. Ab – Kadcyla (TDM-1): an Ab-drug conjugate, Herceptin attached to a chemo drug DM-1. – Perjeta (Pertuzumab ): Mc. Ab – Tykerb (Lapatinib): an oral drug that targets the Her 2 protein.

PI 3 K/Akt/m. TOR pathway Growth factor receptor

PI 3 K/Akt/m. TOR 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. • PI 3 K inhibitors showed synergistic activity with cytotoxic and targeted agents, and have restored sensitivity to these drugs •

PI 3 K/Akt/m. TOR pathway • • • Afinitor: approved for RCC and ER+ BC Torisel: approved for RCC Buparlisib (BKM 120): an oral pan-PI 3 K inhibitor. BYL 719 : PI 3 K a inhibitor XL 147: a selective PI 3 K inhibitor, XL 765: a dual m. TOR and PI 3 K inhibitor Idelalisib: PI 3 K d inhibitor, ? approval for CLL Pictilisib (GDC-0941): PI 3 K a/d inhibitor IPI – 145: PI 3 K d/g inhibitor

Cyclin-Dependent Kinase 4 and 6 (CDK 4/6) Pathway • Palbociclib - "breakthrough therapy" designated by FDA in 2013. • The phase II PALOMA-2 trial: • The phase III PALOMA-3 trial: • LEE 011: the most selective CDK 4/6 inhibitor • LY 2835219: CDK 4/6 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) • 1 st generation: Iressa (gefitinib) Tarceva (Erlotinib) 2 nd generation: Gilotrif (Afatinib) Neratinib Dacomitinib • 3 rd generation: CO-1686 AZ 9291 WZ-4002 HM 61713

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

ALK/ROS 1 pathway • Xalkori (Crizotinib) • Zykadia (Ceritinib), approved on 5/1/2014 • CH 5424802 • AP 26113

Foundation Medicine, Inc. • The company offers Foundation. One, 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: WNK 1, TP 53, JAK 1, DCHS 2, ITSN 2, ADH 8 A 1 • Favorable prognosis: ATXN 7, MST 1, HGF, PLXNA 3, CSDE 1 • • • TP 53: vaccine, gene therapy, WEE-1 inhibitor, Kevetrin PARP: PARP inhibitors ESR: alternative endocrine therapy JAK 1: JAK 1 inhibitors m. TOR: m. TOR inhibitors

VEGF pathway • Avastin: a Mc. Ab 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 m. CRPC

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) – MPDL 3280 A (Roche's Genentech) – MEDI 4736 (Aztra. Zeneca)

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 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).

Chronic Lymphocytic Leukemia • Median survival: 15 -20 years • Ibrutinib is 1 st BTK inhibitor approved for CLL in Feb, 2014 • Idelalisib is PI 3 K inhibitor waiting for approval for CLL

Chronic Lymphocytic Leukemia • BTK inhibitors • PI 3 K inhibitors – Ibrutinib – CC-292 – ONO-4059 – ACP-196 – Idelalisib – GS-9820 – IPI-145 – AMG 319 – TGR-1202 – SAR 245408 • Syk inhibitors – GS-9973 – Cerdulatinib • BCL 2 inhibitors – ABT - 199 – AT - 101

Personalized Cancer Medicine Will Win the War on Cancer

Cancer Awareness Program for Patient Advocate & Public Education for Public Dallas Cancer Specialists 315 N. Shiloh Road, Suite 101 Garland, Texas 75042 972 -487 -8866