T A R G E T E D T H E R A P I E S F O R C A N C E R

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1 1. What are targeted therapies? 2. How do targeted therapies work? 3. What are some of the different types of targeted therapy? 4. What are the potential benefits compared to conventional chemotherapy? 5. What targeted therapies are Boehringer Ingelheim developing? 1. WHAT ARE TARGETED THERAPIES? The emergence of effective cancer chemotherapy is one of the major medical advances of the second half of the 20th century. In certain cancers, such as childhood acute lymphoblastic leukaemia and subgroups of Hodgkin s disease and non-hodgkin s lymphoma, chemotherapy is often curative; and the promise of long-term survival makes therapy well worth the risk of adverse effects. However, traditional chemotherapy is indiscriminate and will affect not only the rapidly proliferating cancer cells but also normal healthy cells. These toxic chemotherapeutic agents are being supplemented by a new generation of therapies that recognise specific targets in or on cancer cells. These targeted therapies hold the promise of improved efficacy and fewer side effects. The term targeted therapies refers to a group of agents that includes: Signal-transduction inhibitors Angiogenesis inhibitors Cell cycle kinase inhibitors Monoclonal antibodies Gene therapy 2. HOW DO TARGETED THERAPIES WORK? Targeted cancer therapies interfere with cancer cell growth and division in different ways and at various points during the development, growth and spread of cancer. Rather than having broad cytotoxic effects, many of these therapies focus on specific proteins that are involved in signalling processes. By blocking the signals that tell cancer cells to grow and divide uncontrollably, targeted cancer therapies can help to stop the growth and division of cancer cells. 3. WHAT ARE SOME OF THE DIFFERENT TYPES OF TARGETED THERAPY? Signal-transduction Inhibitors Small molecule therapies block specific enzymes and growth-factor receptors that are involved in cancer cell growth. These treatments are also called signal-transduction inhibitors. Cell proliferation, differentiation and programmed cell death (apoptosis) are tightly regulated in healthy tissues by a variety of external signals working via receptors that activate intracellular signal-transduction pathways. Cancer cells acquire genetic mutations that alter these signal-transduction pathways, resulting in malignant cells that PAGE 1 TARGETED THERAPIES BACKGROUNDER

2 proliferate uncontrollably and that do not respond to the signals that normally activate apoptosis. This disruption stems from the over-activity of multiple signalling pathways, for example at least one member of the ErbB Family is dysregulated in over 90% of all solid tumours, including lung, breast and head and neck cancers. Alteration of the ErbB Family leads to uncontrolled tumour cell growth and spread. Inhibition of one receptor type alone may not be sufficient for optimal inhibition of tumour cell proliferation and survival. Angiogenesis Inhibitors Angiogenesis, or the growth of new blood vessels, is an important process occurring in the body, both in health and in disease. In a healthy body, angiogenesis occurs in wound healing to restore blood flow to damaged tissues. However, excessive angiogenesis occurs in diseases such as cancer, 1 in which the new blood vessels feed tumours with oxygen and nutrients, encouraging further growth, and allowing tumour cells to escape into the circulation, leading to growth of secondary tumours or metastases. 2 Angiogenesis is driven by signalling via three key receptor tyrosine kinases vascular endothelial growth factor receptors (VEGFR) platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). The VEGF, FGF and PDGF signalling pathways have been shown to be critical for tumour growth and metastasis. 3 In addition, because some tumours harbour an over-amplification of the FGFR or PDGFR genes, inhibition of these pathways may provide an additional, direct antitumour effect. Furthermore, in response to VEGFR blockade, FGFR signalling may also serve as an escape pathway for tumour growth. 3 Therefore, PAGE 2 TARGETED THERAPIES BACKGROUNDER

3 inhibition of multiple pathways including the FGFR pathway may inhibit tumour escape mechanisms. 3 As angiogenesis plays a pivotal role in the growth of all solid tumours, angiogenesis inhibitors are being investigated in clinical studies in a broad range of cancers, including: breast, prostate, brain, pancreatic, lung and ovarian, as well as some leukaemias and lymphomas. Cell Cycle Kinase Inhibitors The cell cycle describes the series of events between one cell division (mitosis) and the next. It is the process by which a single cell forms identical sets of daughter cells. Cell division is essential for many of the body s functions, including reproduction, growth, and tissue repair. Disruption of this process is a fundamental feature of cancer. Cell cycle kinases, such as polo-like kinase 1 (Plk1), are proteins that control the highly ordered, sequential, multi-step processes of cell division, such as DNA synthesis and formation of the mitotic spindle. The mitotic spindle is vital for successful cell division. Many regulatory proteins and mechanisms exist to ensure proper progression and completion of the cell cycle. 4 Plks are members of a family of serine/threonine kinases that are important regulators of cell cycle progression. Over-expression of Plk1 is associated with a poor prognosis in many cancers. 5,6 In vivo tumour models suggest that inhibition of Plk1 results in tumour growth inhibition and regression. Plk1 may therefore be a suitable target for cancer therapy. 7,8 Monoclonal antibodies Monoclonal antibodies (mabs) are part of the so-called biological group of therapies for the treatment of cancer. The molecules are designed to mimic the antibodies naturally produced by the body s immune system in order to have specific effects on cancer cells: Highlight the cancer cells to the immune system. Often the body does not recognise cancer cells as a threat. A mab can be designed to attach to specific parts of the cancer cells flagging to the immune system that the cell is an enemy. The body s natural immune response is then initiated and begins to attack the cancer cells. Block growth signals. Cancer cells frequently make more copies of the growth factor receptors than healthy cells, making them grow and proliferate faster. The mabs can block the growth factor receptors preventing the growth signal from getting through thereby stopping the cells from dividing and multiplying. PAGE 3 TARGETED THERAPIES BACKGROUNDER

4 Prevent new blood vessels from forming. Cancer cells and healthy cells rely on blood vessels to provide the oxygen and nutrients needed for cell growth. Cancer cells send out growth signals to attract new blood vessels (angiogenesis) which is a key factor in tumour growth and metastasis. MAbs can block these growth signals which may help prevent a tumour from developing a sufficient blood supply. Transport radiation to cancer. Radiation-linked mabs have been developed that combine a mab with a radioactive particle. The mab directs the low level radiation particle directly to the cancer cells, providing a lower dose of radiation over a longer period of time. 9 Examples of mabs are rituximab for the treatment of non-hodgkin s lymphoma and trastuzumab for the treatment of breast cancer. Other mabs are being studied for a broad range of cancers, including colorectal, lung, prostate and brain. Gene Therapy Gene therapy is an experimental treatment that involves introducing genetic material into a person s cells to fight or prevent disease. Humans have between 30,000 and 40,000 genes the biological units of heredity that determine traits such as hair and eye colour, as well as more subtle characteristics such as the ability of blood to carry oxygen. Genes are located on chromosomes inside cells and carry the instructions that allow cells to produce specific proteins, such as enzymes. Researchers are studying several ways to treat cancer using gene therapy, including: Replacing or blocking altered genes with healthy genes Stimulating the body s natural ability to attack cancer cells Inserting genes into cancer cells to make them more responsive to chemotherapy or other treatments Preventing cancer cells from developing new blood vessels 4. WHAT ARE THE POTENTIAL BENEFITS COMPARED TO CONVENTIONAL CHEMOTHERAPY? Chemotherapy involves using cytotoxic agents to treat cancer. These treatments are also toxic to healthy tissues and consequently are associated with a high level of side effects and complications. As these agents are often used at the limits of toxicity and efficacy in order to ensure optimal tumour response, maximising efficacy and safety are the main considerations in chemotherapy practice. Side effects and complications from treatment include: Nausea and vomiting Suppression of the immune system, leading to infections and blood disorders such as low white blood cell count and anaemia Hair loss Renal and hepatic toxicity Hypersensitivity reactions PAGE 4 TARGETED THERAPIES BACKGROUNDER

5 Although many chemotherapy agents dramatically affect the course of the disease, success is far from universal. Certain tumour types are relatively resistant to such anticancer drugs. In other instances, a marked response to treatment occurs at first but, over time, the disease process recurs and treatments become ineffective. This is referred to as drug resistance. Conversely, targeted therapies, by their very nature, deliver their therapeutic effect directly to the cancer cell. This can often be achieved at doses below the maximum tolerated dose and so tumour response can be seen with the potential for fewer and less toxic side effects, thereby offering improved quality of life for patients and their families. In addition, many targeted treatments in development overcome the problems of resistance seen with the more broad spectrum conventional chemotherapy. Of most significance is that targeted therapies will give physicians an opportunity to improve the tailoring of treatment with the potential of individualising treatment based on the unique set of molecular targets produced by the patient s tumour. Modern treatment approaches frequently combine conventional chemotherapy with targeted therapy, in particular in late stage disease. Targeted therapies in most cases do not increase the dose-limiting toxicities of the chemotherapy. 5. WHAT TARGETED THERAPIES IS BOEHRINGER INGELHEIM DEVELOPING? Boehringer Ingelheim has a long-term commitment to deliver tomorrow s cancer therapies by discovering and developing novel treatment options that combine groundbreaking science with high therapeutic value for patients, physicians and healthcare providers. Building on breakthrough science to develop targeted therapies biologicals and small molecules Boehringer Ingelheim is focussing its research in areas of unmet medical need including both solid and haematological cancers. The current focus of Boehringer Ingelheim s late stage cancer research includes compounds in three areas that are relevant across a variety of cancers: PAGE 5 TARGETED THERAPIES BACKGROUNDER

6 . Signal transduction inhibition with afatinib*, the first irreversible ErbB Family Blocker approved in the U.S, Europe, Taiwan and Mexico for use in patients with Epidermal Growth Factor Receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) Angiogenesis inhibition with the compound nintedanib*, a Triple Angiokinase Inhibitor (TAI) Cell-cycle kinase inhibition with the compound volasertib*, an inhibitor of Plk REFERENCES 1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285: Folkman J. What is the evidence that tumours are angiogenesis dependent? J Natl Cancer Inst 1990;82: Santos ES, Gomez JE, Raez LE. Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor. Invest New Drugs. 2012;30: Johnson DG, Walker CL. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 1999;39: Eckerdt F, Yuan J, Strebhardt K. Polo-like kinases and oncogenesis. Oncogene 2005;24: Strebhardt K, Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer 2006;6: Liu X, Erikson RL. Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A 2003;100: Lénárt P, Petronczki M, Steegmaier M, et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol 2007;17: Monoclonal antibody drugs for cancer treatment: How they work. Mayo Clinic. [Online] Available at: [Last Accessed April 2011]. *In the EU, Taiwan and Mexico, afatinib is approved for use in patients with distinct types of NSCLC under the brand name GIOTRIF, and in the U.S. under the brand name GILOTRIF TM. Afatinib is under regulatory review by health authorities in Asia and other countries. Nintedanib and volasertib are investigational compounds and are not yet approved. Their safety and efficacy have not yet been fully established. PAGE 6 TARGETED THERAPIES BACKGROUNDER