1. Special Topics Cancer Pharmacology II Joseph De Soto MD, PhD, FAIC

2. Overview The targets of traditional cytotoxic agents tend to be multiple and broad an as such modern combinations of chemotherapeutics are used to treat most cancer due to their superiority over single agents. Indeed, dose intense therapies tend to be inferior to normal therapy.Yet, due to overlapping molecular pathways and toxicities the individual doses within combinations must be reduced. Indeed, dose intense therapies tend to be inferior to normal therapy. Targeted therapies Targeted therapies tend to do less collateral damage to critical cellular mechanisms and tend to be less toxic and most of the pathways blocked are those that might desensitize cells to their suicide mechanism.

3. Introduction The principal obstacles to the clinical efficacy of chemotherapy have been the toxicity to the normal tissues of the body and the development of cellular drug resistance.The principal obstacles to the clinical efficacy of chemotherapy have been the toxicity to the normal tissues of the body and the development of cellular drug resistance. The advances in molecular biology and genetics have provided insights into the understanding of the molecular pathways by which chemotherapy exerts its cytotoxic activity and how genetic instability confers resistance to therapyThe advances in molecular biology and genetics have provided insights into the understanding of the molecular pathways by which chemotherapy exerts its cytotoxic activity and how genetic instability confers resistance to therapy

6. Tyrosine Kinase Inhibitors Tyrosine kinases are important protein receptors involved in cell cycle progression, cellular migration, cellular proliferation, cellular survival, and angiogenesis.Tyrosine kinases are important protein receptors involved in cell cycle progression, cellular migration, cellular proliferation, cellular survival, and angiogenesis. The extracellular domain of tyrosine kinases bind to a ligand which causes a conformational change and eventual dimerization of the tyrosine kinase receptor.The extracellular domain of tyrosine kinases bind to a ligand which causes a conformational change and eventual dimerization of the tyrosine kinase receptor. Highly conserved intracellular portions of the dimerized receptor phosphorylate each other on tyrosine residues and second messengers.Highly conserved intracellular portions of the dimerized receptor phosphorylate each other on tyrosine residues and second messengers. There are two major forms of tyrosine kinase inhibitors 1) small molecule and 2) antibodies. There are two major forms of tyrosine kinase inhibitors 1) small molecule and 2) antibodies.

7. Tyrosine Kinase

8. Small Molecules vs Antibodies

9. Inhibitors of Angiogenesis Angiogenesis is a critical step in tumor progression. New blood vessel growth is important for tumors whether primary or metastasized and is necessary for tumor growth above 2 mm in volume. Angiogenesis is promoted during the menstrual cycle, pregnancy, wound healing, and in cancer.Angiogenesis is a critical step in tumor progression. New blood vessel growth is important for tumors whether primary or metastasized and is necessary for tumor growth above 2 mm in volume. Angiogenesis is promoted during the menstrual cycle, pregnancy, wound healing, and in cancer. The following tyrosine kinase signaling pathways are important in angiogenesis in the following order:The following tyrosine kinase signaling pathways are important in angiogenesis in the following order: VEGF : vascular endothelial growth factorVEGF : vascular endothelial growth factor PDGF : platelet derived growth factorPDGF : platelet derived growth factor cKIT : Mast/stem cell growth factor receptor (actually stimulates blood growth and not blood vessel growth ) cKIT : Mast/stem cell growth factor receptor (actually stimulates blood growth and not blood vessel growth ) FGF : fibroblast growth factorFGF : fibroblast growth factor By inhibiting these pathways, one inhibits angiogenesis and as a consequence cell survival, migration and vascular permeability. (These are also factors in cellular metastasis)By inhibiting these pathways, one inhibits angiogenesis and as a consequence cell survival, migration and vascular permeability. (These are also factors in cellular metastasis)

10. Bevacizumab Bevacizumab (Avastin)is an angiogenesis inhibitor, it slows the growth and formation of new blood vessels. It is used to treat the following cancers: colorectal, lung, glioblastoma, kidney and ovarian*.Bevacizumab (Avastin)is an angiogenesis inhibitor, it slows the growth and formation of new blood vessels. It is used to treat the following cancers: colorectal, lung, glioblastoma, kidney and ovarian*. Bevacizumab is a humanized monoclonal antibody that produces angiogenesis inhibition by inhibiting vascular endothelial growth factor ABevacizumab is a humanized monoclonal antibody that produces angiogenesis inhibition by inhibiting vascular endothelial growth factor A Combination with FOLFOX ( 5-FU, Oxaloplatin, Leucovorin) in colorectal; metastatic disease.Combination with FOLFOX ( 5-FU, Oxaloplatin, Leucovorin) in colorectal; metastatic disease. Used with 5-FU, Carboplatin, Paclitaxel…ovarian, non – small cell.Used with 5-FU, Carboplatin, Paclitaxel…ovarian, non – small cell.

11. Sunitinib Sunitinib is a small molecule that inhibits Vascular Endothelial Growth Factor Receptors 1 + 2 (VEGF R 1/2), Platelet Derived Growth Factor (PDGF) and cKIT inhibiting angiogenesis.Sunitinib is a small molecule that inhibits Vascular Endothelial Growth Factor Receptors 1 + 2 (VEGF R 1/2), Platelet Derived Growth Factor (PDGF) and cKIT inhibiting angiogenesis. It is used to treat: Renal Cell Carcinoma (RCC), Pancreatic neuroendocrine tumors, Imatinib resistant Gastro Intestinal Stromal Tumors (GIST)It is used to treat: Renal Cell Carcinoma (RCC), Pancreatic neuroendocrine tumors, Imatinib resistant Gastro Intestinal Stromal Tumors (GIST) Special toxicity: Hand Foot Syndrome:Special toxicity: Hand Foot Syndrome:

12. Renal Cell Carcinoma

13. Thalidomide & Lenalidomide Thalidomide and its analog lenalidomide (revlimid) are thought to decrease levels of VEGF and interleukin -6 and hence, decrease angiogenesis and inflammation.Thalidomide and its analog lenalidomide (revlimid) are thought to decrease levels of VEGF and interleukin -6 and hence, decrease angiogenesis and inflammation. Lenalidomide in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. It is also indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.Lenalidomide in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. It is also indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. Special Toxicity: PhocomeliaSpecial Toxicity: Phocomelia

15. Antiangiogenesis Toxicities Effect: Expensive medications with a small effect on overall survival and a moderate effect on disease progression, large effect on some symptoms. Effect: Expensive medications with a small effect on overall survival and a moderate effect on disease progression, large effect on some symptoms. Among the common toxicities of Anti-Angiogenic Tyrosine Kinase Inhibitors are: Among the common toxicities of Anti-Angiogenic Tyrosine Kinase Inhibitors are: 1.Bleeding 2.Disturbed wound healing 3.Gastro-intestinal perforation 4.Hypertension 5.Fatigue 6.Arterial thrombotic events

16. Epidermal Growth Factor Inhibitors This family of receptors plays a large role in growth, metastasis, resistance to apoptosis, and resistance to some chemotherapeutic compounds.This family of receptors plays a large role in growth, metastasis, resistance to apoptosis, and resistance to some chemotherapeutic compounds. There are 4 types of Epidermal Growth Factor Receptors:There are 4 types of Epidermal Growth Factor Receptors: EGFR1: EGFREGFR1: EGFR EGFR2: Her2/c-neu REGFR2: Her2/c-neu R EGFR3Her3 REGFR3Her3 R EGFR4:Her 4 REGFR4:Her 4 R The active dimers are: EGFR/EGFR, EGFR/HER2, HER2/HER2, HER2/HER3, HER2/HER4The active dimers are: EGFR/EGFR, EGFR/HER2, HER2/HER2, HER2/HER3, HER2/HER4 Note: HER2 dimerizes with each of the other receptor subtypes Note: HER2 dimerizes with each of the other receptor subtypes

18. Trastuzumab Trastuzumab (Herceptin) is s a monoclonal antibody that interferes with the HER2/neu receptor. It is used to treat breast cancer alone or in combination with chemotherapy.Trastuzumab (Herceptin) is s a monoclonal antibody that interferes with the HER2/neu receptor. It is used to treat breast cancer alone or in combination with chemotherapy. Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer doesn't overexpress HER2, trastuzumab will have no beneficial effect.Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer doesn't overexpress HER2, trastuzumab will have no beneficial effect. In the routine clinical laboratory, the most commonly employed methods for this are immunohistochemistry (IHC) fluorescent in situ hybridisation (FISH).In the routine clinical laboratory, the most commonly employed methods for this are immunohistochemistry (IHC) fluorescent in situ hybridisation (FISH).

19. Lapatinib Lapatinib (Tykerb), is a small molecule inhibitor of EGFR (Erb1) and Her-2/neu (ErbB2) thereby Inhibiting EGFR/EGFR; EGFR/HER2; HER2/HER2 dimerization.Lapatinib (Tykerb), is a small molecule inhibitor of EGFR (Erb1) and Her-2/neu (ErbB2) thereby Inhibiting EGFR/EGFR; EGFR/HER2; HER2/HER2 dimerization. It is used for metastatic breast cancer alone or in combination with capecitabine who have failed trastuzumab and chemotherapy.It is used for metastatic breast cancer alone or in combination with capecitabine who have failed trastuzumab and chemotherapy. Lapatinib is also used as a treatment for women's breast cancer in treatment naive, ER+/EGFR+/HER2+ breast cancer patientsLapatinib is also used as a treatment for women's breast cancer in treatment naive, ER+/EGFR+/HER2+ breast cancer patients

20. Toxicities Effect: The effectiveness of the drug correlates with the severity of the rash. That is the worse the rash the better the drug is working. Modest increase in progression free survival and small increase in overall survival.Effect: The effectiveness of the drug correlates with the severity of the rash. That is the worse the rash the better the drug is working. Modest increase in progression free survival and small increase in overall survival. Among the common toxicities of Epidermal Growth Factor Type Inhibitors are:Among the common toxicities of Epidermal Growth Factor Type Inhibitors are: 1.Acne form rashes1.Acne form rashes 2.Diarrhea2.Diarrhea 3.Constipation3.Constipation 4.Vomiting4.Vomiting 4.Stomatitis4.Stomatitis

21. Proteosome Inhibitors Proteosome inhibitors are irreversible inhibitors of the proteosome which is important for the intracellular degradation of proteins.Proteosome inhibitors are irreversible inhibitors of the proteosome which is important for the intracellular degradation of proteins. Bortezomib (Velcade) is approved for the treatment of multiple myeloma and is based on a objective response rate of 28% in patients who were heavily pretreated and refractory to their most recent therapy.Bortezomib (Velcade) is approved for the treatment of multiple myeloma and is based on a objective response rate of 28% in patients who were heavily pretreated and refractory to their most recent therapy. Other hematological cancers may be amiable to bortezomib including non-Hodgkins lymphoma, and Waldenstroms macroglobinemiaOther hematological cancers may be amiable to bortezomib including non-Hodgkins lymphoma, and Waldenstroms macroglobinemia

23. Toxicities Thrombocytopenia is seen in 28% of patients, due to the inhibition of platelet budding from megakaryoctes.Thrombocytopenia is seen in 28% of patients, due to the inhibition of platelet budding from megakaryoctes. Neuropathic pain occurs in 12 % of patients, when this occurs the medication must be stopped or neurological damage will become permanent.Neuropathic pain occurs in 12 % of patients, when this occurs the medication must be stopped or neurological damage will become permanent. Neutropenia, anemia, diarrhea, and constipation are other side effects.Neutropenia, anemia, diarrhea, and constipation are other side effects.

24. Anti-Estrogens Anti-estrogens such as tamoxifen (Nolvadex), Raloxifene (Evista) and Fulvestrant (Faslodex) are used to treat pre- menopausal breast cancer and occasionally post-menopausal breast cancer.Anti-estrogens such as tamoxifen (Nolvadex), Raloxifene (Evista) and Fulvestrant (Faslodex) are used to treat pre- menopausal breast cancer and occasionally post-menopausal breast cancer. These agents bind to the estrogen receptor and modulate the activity of the estrogen/receptor complex as it binds to the estrogen response element (ERE) of DNA hence, modulating DNA synthesis.These agents bind to the estrogen receptor and modulate the activity of the estrogen/receptor complex as it binds to the estrogen response element (ERE) of DNA hence, modulating DNA synthesis. These agents may be used as preventive agents, alone or in combination with chemotherapy in those who have cancer ….the latter depending on the cancer subtype and/or stage of breast cancer.These agents may be used as preventive agents, alone or in combination with chemotherapy in those who have cancer ….the latter depending on the cancer subtype and/or stage of breast cancer.

26. Toxicities Tamoxifen increases the risk of endometrial cancer, reduces cognition, early bone fusion and thromboembolism.Tamoxifen increases the risk of endometrial cancer, reduces cognition, early bone fusion and thromboembolism. Raloxifene increases bone density which is beneficial and does not increase the risk of endometrial cancer. Increases risk of thromboembolism and reduced cognition.Raloxifene increases bone density which is beneficial and does not increase the risk of endometrial cancer. Increases risk of thromboembolism and reduced cognition. Falsodex increases risk of osteoporosis, thromboembolism, reduces cognition, and early bone fusion.Falsodex increases risk of osteoporosis, thromboembolism, reduces cognition, and early bone fusion.

27. Aromatase Inhibitors Aromatase inhibitors (AIs) are used in the treatment of breast cancer and ovarian cancer in postmenopausal women.Aromatase inhibitors (AIs) are used in the treatment of breast cancer and ovarian cancer in postmenopausal women. Aromatase converts androgens into estrogens, the latter of which stimulate the growth of breast and ovarian cancer.Aromatase converts androgens into estrogens, the latter of which stimulate the growth of breast and ovarian cancer. There are two types of aromatase inhibitors: Irreversible steroidal inhibitors like exemestane (Aromasin), and non- steroidal inhibitors like anastrozole (Arimidex) and letrozole (Femara).There are two types of aromatase inhibitors: Irreversible steroidal inhibitors like exemestane (Aromasin), and non- steroidal inhibitors like anastrozole (Arimidex) and letrozole (Femara). Side effects include an increased risk for developing osteoporosis, arthritis, and arthralgia. Side effects include an increased risk for developing osteoporosis, arthritis, and arthralgia.

28. Conclusions Targeted drugs exert their best results when used in combination with cytotoxic agents.Targeted drugs exert their best results when used in combination with cytotoxic agents. Targeted drugs may be useful as single agents in the metastatic setting where there is no hope for a cure or remission.Targeted drugs may be useful as single agents in the metastatic setting where there is no hope for a cure or remission.