1. Anticancer drugs Specific tumor-targeted therapy, Immunomodulators, Anticancer Vaccines

2. Specific therapy, tumor-targeted (biological) therapy  Drugs more targeting cancer-specific processes than processes common to all cells.  Because these drugs are not directly toxic, and because they preferentialy affect cancer cells, they offer the hope of being specific with few side effects.

3. Specific Therapies and their Targets Drugs that affect growth factors and their receptors Small-molecule specific inhibitors of intracellular kinases (usually tyrosine kinases) Drugs that bind to antigens on lymphocytes (and leukocytes) Neo-angiogenesis inhibitors Proteasome inhibitors etc….

4. Specific therapy, tumor-targeted (biological) therapy  Blocking a single pathway in a cancer cell may be enough to slow it down, but it often does not inhibit the cancer enough to kill it.  Therefore, many specific cancer drugs are currently being used together with traditional chemotherapy.

5. Specific Therapy: monoclonal antibodies and fusion proteins  Administered i.v. in one to several week intervals  Monoclonal antibodies against membrane receptors or surface antigens  Receptors for growth factors (EGFR, HER2-neu, VEGFR) – solid cancers  Membrane antigens on leukocytes (CD20, CD52 atc.) – hematological malignancies  Monoclonal antibodies and fusion proteins (=circulating complex of the receptor attached to IgG) against growth factors and other proteins  Growth factors (VEGF, IL-6 etc.)  Adhesive molecules…

6. Specific Therapy  Small-molecule inhibitors of intracellular tyrosine kinases and other kinases are not proteins administered orally  some small-molecule inhibitors (e.g., sorafenib, sunitinib, imatinib, dasatinib) have multiple targets, inhibit several kinases

8. Examples of monoclonal antibodies against specific receptors  Trastuzumab (Herceptin™) is one of the major developments in the treatment of breast cancer over recent years.  It is a mouse recombinant humanised monoclonal antibody IgG1. against HER-2 neu human epidermal growth factor receptor (ErbB2) which is overexpressed in breast cancer cells in approximately 20% of patients.

9. Examples of monoclonal antibodies against specific receptors  The overexpression of HER-2 is detected by immunohisto- chemistry on sections of fixed tumours.  The response rate of patients overexpressing HER-2 is over 50%. The responses are long-lasting (several months to two to three years) in patients with cancers which are resistant to usual chemotherapy.  The majory toxicity is cardiotoxicity which is augmented if the patient received doxorubicin as a part of therapy

10. Monoclonal antibodies against specific receptors  cetuximab is a chimeric monoclonal antibody that binds to the EGF receptor (epidermal growth factor receptor)  the net effects are inhibition of tumor growth, invasion, angiogenesis and metastasis  monotherapy or in combination with chemotherapy in first-, second- or third-line tretments for metastatic colorectal cancer in patients with wild-type KRAS (Kirsten rat sarcoma viral oncogene homolog, a GTPase), an early molecule in many signal transduction pathways  testing prior therapy is performed  tumours with mutant KRAS are considered to be resistant and the therapy is not indicated

11. Monoclonal antibodies against specific receptors  Rituximab is a chimeric murine/human monoclonal antibody against the CD20 antigen.  This treatment is a major step in the treatment of lymphoma.  It is active against malignant cells presenting antigen CD20, i.e. in follicular lymphoma (stage III and IV), in aggressive diffuse large B cell non-Hodgkin’s lymphoma.  The response rates to rituximab in B cell follicular non-Hodgkin’s lymphoma or in low grade lymphoma, relapsing or resisting to chemotherapy, are in the range of 50%. The responses are generally long-lasting.

12. Specific kinases and cancer  One key feature of cancer cells is their ability to devide in the absence of external signals such as growth factors.  In the normal cells, growth factors that are excreted by other cells bind to receptors on the cell surface, stimulating the cell to divide.  Cancerous cells turn on the pathway in the absence of the growth factor.  This may occur because of a mutation in a kinase or phosphatase gene.

13. Specific kinases and cancer  In one example, chronic myeloid leukemia, a particular chromosomal transloction (termed the Philadelphia chromosome) has been identified that creates a novel kinase that is permanently active.  Bcr-Abl tyrosine kinase affects numerous signal transduction pathways that are essential for leukaemic transformation, including increased cellular proliferation, and antiapoptotic effects.

14. Small-molecule inhibitors of specific kinases  Two of the most succesfull drugs are small-molecule kinase inhibitors imatinib (Gleevec) and ZD 1839 (Iressa) given orally.  During the chronic phase, the remission rate is very high (up to 90%) with a complete clearance of the cytogenetic abnormality in about 40% of these cases. This remission can last for long periods.  During the blastic transformation of chronic myeloid leukaemia (where survival is generally around 3 months), approximately 50% of patients respond, 10% of whom have a complete cytogenetic response. Median survival is 8 months, but 30% of patients live longer than 15 months.  The toxicity of imatinib mesylate is low: nausea, diarrhoea, myalgias, periorbital oedema, various skin rashes.  Other more recently introduced kinase inhibitors: desatinib, nilotinib…

15. Angiogenesis Inhibitors  Tumors produce factors that stimulate the formation of blood vessels (neoangiogenesis).  Approaches to the inhibition of angiogenesis: Inhibitors of angiogenesis activation: The drugs in this class of angiogenesis inhibitors work by blocking the cascade of events that cause blood vessels to form. Matrix metalloproteinases inhibitors: Growing blood vessel cells secrete enzymes called matrix metalloproteinases that are able to digest the extracellular matrix and allow blood vessels to invade the area and supply the tumor with nutrients. Inhibition of this process is the target of several drugs. Endothelial cell inhibitors inhibit angiogenesis by acting to prevent the growth or activities of the endothelial cells that form the blood vessels.

16. Different approaches to targeting of the VEGF pathway: 1 2 3 4

17. Angiogenesis Inhibitors  Bevacizumab or Avastin™ is a chimeric murine/human monoclonal antibody, which specifically binds to vascular endothelial cell growth factor (VEGF).  The current indication is the first-line treatment of metastatic colorectal carcinoma in association with chemotherapy comprising 5-FU.  A significantly increased total survival and disease free survival have been observed.  The small molecule inhibitors which penetrates the cell membrane and inhibits the intracellular kinase part of the receptor: sunitinib, sorafenib

18. Angiogenesis Inhibitors  Thalidomide and pomalidomide, a derivative of thalidomide, are anti-angiogenic are used as a treatment for relapsed and refractory multiple myeloma.

19. Proteasomes and cancer  Most cellular proteins have a limited lifespan from a few minutes to a few weeks. The proteins are destroyed in two different ways: lysosomial system (10-20% superficial proteins) and proteasome system (close to 80% of intracellular proteins).  Proteasomes control the half-life of many short-lived regulatory proteins, such as those involved in the cell cycle.  Therefore, proteasome malfunction can lead to abnormal regulation of the cell cycle and uncontrolled cell proliferation.

20. Proteasomes and cancer  Inhibition of proteasome function causes cell cycle arrest and cell death.  Tumor cells are more susceptible to these effects than normal cells, in part because they divide more rapidly and in part because many of their normal regulatory pathways are disrupted.

21. Proteasome inhibitors  The most advanced molecule in clinical setting is bortezomib.  The first clinical studies concerned myeloma.  In a major phase II study, Bortezomib was administered to patients relapsing after several chemotherapy regimens. A 35% response rate was observed with 10% of complete responses. Duration of responses was around 12 months.  Many studies are currently in progress in breast cancer, hormone independent prostate cancer, lung cancer and lymphoma.

22. Specific Therapy  The molecular targets for tumour-specific drugs are not overexpressed in a single cell type, but rather on various malignant and normal tissues.  For example, CD 20 is present on lymphoma and normal lymphoid cells and VEGFR is present on normal and tumor-associated vasculature.  TOXICITY

23. Toxicity of Specific Therapies  Drugs against VEGF: severe hypertension in 3-16% of patients, bleeding, impaired wound healing,  Drugs against EPGF: skin toxicity (acneiformic rash 80%, dry and itchy skin, inflammation).  Mucositis: trastuzumab,cetuximab, erlotinib, gefitinib  Diarrhea: small-molecule tyrosine-kinase inhibitors (TKI)  Proteinuria and thrombosis: bevacizumab  Myelosuppression including neutropenia, anemia and thrombocytopenia have been described as side effects related to various TKI, most notably sorafenib and sunitinib

24. Conjugated antibodies in cancer treatment Carter P: Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001

26. Immunotherapy  Unfortunately many cancer cells tend to go unnoticed by the immune system because they originate from normal body cells.  Cancer cells often do not elicit a significant immune response.  Immunotherapy is believed to potentially kill the residual tumor cells after regional therapies and classical chemotherapy

27. Biological response modifiers  Biological response modifiers are compounds that are used to treat cancer by altering or augmenting naturally occurring processes within the body. Immunotherapy with the modifiers is aimed to enhance the activity of the immune system to increase the body's natural defense mechanisms against cancer.  The role of cytokines in the body's defenses makes them appealing targets for treating some cancers. Cytokines are normally found in very small amounts. When used as cancer treatments the concentrations used are greatly increased.  The cytokines most frequently used to treat cancer are interleukin-2 and alpha-interferon.  These compounds do have severe side effects when used at the high doses necessary for cancer treatment and their effectiveness varies depending on the cancer type.  IL-2 causes vascular leak leading to edemas

28. Cancer vaccines  The purpose of cancer vaccines is to stimulate the body's defenses against cancer by increasing the response of the immune system.  Tumor vaccines usually contain proteins found on or produced by cancer cells.  By administering forms of these proteins and other agents that affect the immune system, the vaccine treatment aims to involve the patient's own defenses in the fight to eliminate cancer cells.  Immunotherapy with vaccines is stil a new and investigational field in cancer treatment and prevention, and many strategies are being examined in clinical trials.  It is likely that tumor vaccines and other approaches designed to increase the activity of the immune system will continue to be used in combination with other cancer treatments.

29. Cancer vaccines  Sipuleucel-T is a therapeutic vaccine for prostate cancer.  It must be prepared specifically for each patient.  A course of sipuleucel-T treatment consists of three basic steps:  1. A patient's own white blood cells, primarily antigen-presenting cells (dendritic cells), are extracted in a leukapheresis procedure.  2.The blood product is sent to the factory and incubated with a fusion protein (PA2024) consisting of two parts: the antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells, and an immune signaling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the APCs to mature.  3.The activated blood product to the infusion center and re-infused into the patient to cause an immune response against cancer cells carrying the PAP antigen.

30. Cancer vaccines  A complete sipuleucel-T treatment repeats three courses over the span of a month, with two weeks between successive courses  In metastatic prostate cancer, it has extended survival by median 4.1 months (IMPACT Phase III trial data).  The first FDA approved therapeutic vaccine against cancer.  The treatment costs $93,000.

31. Prophylactic vaccines  The recent development and approval of a vaccine that prevents cervical cancer is a tremendous step forward in this field and is a milestone in cancer prevention.  The majority of cervical cancer is believed to be caused by the Human Papillomavirus (HPV).  There are more than 100 variants (subtypes) of HPV but only a small subset are associated with human cancer.  HPV subtypes 16 and 18 are the variants most commonly associated with human cervical cancer.  Several characteristics of HPV make it a good target for vaccine development. The virus is simple, small, and has a stable genome.

32. Prophylactic vaccines  The first preventative cancer vaccine to receive FDA approval is Gardasil®. Gardasil® was designed to prevent infection by four different subtypes of HPV (6, 11, 16, and 18).  HPV types 6 and 11 together, cause 90% of the cases of genital warts while 16 and 18 combined, are responsible for 70% of cervical cancer cases. Gardasil® contains VLPs containing the capsid protein of each of these four strains of HPV.