ttbc-141123013259-conversion-gate01.pptx

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1. Targeted Therapies For Breast Cancer Presented By: Anvita Jadhav Final Year B.Pharm 29/11/2013 1

2. Surgery Radiotherapy Hormonal therapy Chemotherapy Treatments 2

3. Targeted Cancer Therapies Drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth & progression. Most researchers consider it as new approach to treating breast cancer that targets the cell signaling pathways of cancer cells. More selective for cancer cells. Blocking of signals help to stop cancer progression and may induce cancer cell death through apoptosis. The development of targeted therapies requires the identification of good targets. 3

4. In this seminar, we are going to study breast cancer therapies which are targeted for following targets: Tyrosine Kinases Receptors Steroid Receptor Coactivators (SRC) Mammalian Target of Rapamycin (mTOR) & Phosphoinositide 3-kinase (PI3K) Poly-{adenosine diphosphate (ADP)-ribose} polymerase (PARP) 4

5. Class of enzymes which are responsible for phosphorylation of tyrosine residue on targeted proteins. Stimulate multiple signaling pathways responsible for basic cells functions. Several oncogenic tyrosine kinases have been detected in human malignancies. There are two families of tyrosine kinases- Transmembrane receptor kinases & Cytoplasmic non-receptor kinase a) Transmembrane kinases receptor : Human Epidermal Receptor (HER) Insulin like Growth Receptor (IGFR) Fibroblast Growth Factor Receptor (FGFR) Vascular Endothelial Growth Factor Receptor (VEGFR ) Platelet-derived Growth Factor Receptor (PDGFR) b) Cytoplasmic non-receptor kinase: Steroid Receptor Coactivators (SRC) Tyrosine Kinases (TKs) 5

6. Multiple signaling pathways involved in the development, growth, and survival of breast cancer cells mTOR/PI3K/Akt Pathway IP3/DAG Pathway Ras/MAPK Pathway 6

7. ErbB proteins are a four-member family of highly homologous receptor tyrosine kinases comprised of ErbB1 (EGFR, HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). It is also known as ErbB1/HER1, is essential for growth and differentiation of epithelial cells. The expression of EGFR, ligands, and their activating proteases in breast cancers has been intensively studied. Epidermal Growth Factor Receptor Targeting Monoclonal Antibodies: Agent Class of compound Stages IMC-C225 mAb Phase II ABX-EGF mAb Phase II Human Epidermal Receptors (HER) Epidermal Growth Factor Receptor (EGFR) 7

8. The HER2 gene is amplified in approximately 20%-30% of breast cancers. Overexpression HER2 found in breast cancer cells which has also been associated with resistance to chemotherapy and hormone therapy. HER2 target is present in a very high proportion of tumor cells Human E pidermal Receptor 2 Targeting Monoclonal Antibodies:   Agent Class of compound Stages Trastuzumab mAb Approved Trastuzumab–DM-1 mAb-toxin conjugate Approved Human Epidermal Receptor 2(HER2) 8

9. Trastuzumab Trastuzumab DM 1 9

10. Compound Selectivity invitro IC(Nm) Stages EGFR HER2 ZD1839, Gefitinib 27 3700 Marketed OSI-774, Erlotinib 2 350 Marketed GW572016 , Lapatinib 11 9 Marketed CP-724714 4300 8 Phase II Arry-334543 7 2 Phase II CI-1033, PD183805, Canertinib 0.8 19 Phase II BIBW-2992 0.5 14 Phase II AV-412, MP-412 1 18 Phase I AEE788 6 6 Phase II EKB-569, Pelitinib 39 1200 Phase II HKI-272, Neratinib 92 59 Phase II BMS-599626 22 32 Phase I Selected HER Family T yrosine K inase I nhibitors: 10

11. IGF system is composed of ↑ circulating levels of IGF-I are associated with a greater risk of breast cancer in premenopausal women, with an especially high risk among those younger than 50 years. ↑ IGFs resists apoptosis in response to chemotherapy and radiation. IGFBPs is activated by the estrogen, which itself activates expression of IGF-I. Insulin-like Growth Factor Receptor (IGFR) 11

12. Insulin-like growth factor 1 receptor (IGF-1R) Targeting Agents: Agents Regimen Stages IGF-1R Antibodies CP-751,871 Docetaxel Phase II Exemestane Phase II Single agent Phase I AVE1642 / EM164 Faslodex Phase II IMC-A12 (Cixutumumab) Temsirolimus Phase I/ II Capecitabine and Lapatinib Phase II AMG 479 Exemestane or fulvestrant Phase II MK-0646/h7C10 (Dalotuzumab) Single Regimen Phase II Ridaforolimus Phase II Ridaforolimus and exemestane Phase II Dual IGF-1R–insulin receptor inhibitor BMS‑754807 Trastuzumab Phase I/ II Letrozole Phase II 12

13. The fibroblast growth factor (FGF) consist of 18 ligands. FGF1 & FGF23 signal through four high affinity fibroblast growth factor receptor (FGFR1 to FGFR4). Under physiological conditions, the highly complex FGF signaling pathway is tightly regulated. The deregulation of FGF signaling to development of cancer, promoting cancer cell proliferation, survival and migration. Fibroblast Growth Factor Receptor (FGFR) 13

14. Drug class Drug name Target Stages 1 st generation TKIs TKI258 (Dovitinib) FGFR, PDGFR & VEGFR Phase III BMS54021 (Brivanib) FGFR & VEGFR Phase II BIBF 1120 FGFR, PDGFR & VEGFR Phase III Ponatinib ABL, FGFR, PDGFRα, FLT3 & VEGFR2 Phase II E7080 FGFR, PDGFR, VEGFR, KIT, RET Phase I E3810 FGFR1& VEGFR1 to VEGHR3 inhibitor Phase I Sulfatinib FGFR & VEGFR inhibitor Phase I Fibroblast Growth Factor Receptor Targeting Agents: 14

15. Drug class Drug name Target Stages 2 nd generation TKIs AZD 4547 Selective FGFR1, FGFR2 & FGFR3 inhibitor Phase II BGJ398 Selective pan- FGFR inhibitor Phase I FGFR antibodies IMC-A1 FGFR1-IIIc-specific antibody Preclinical GP369 FGFR2 blocking antibody Preclinical PRO-001 FGFR3-specific blocking antibody Preclinical R3Mab FGFR3-specific antibody Preclinical FGFR ligand traps FP-1039 FGF ligand traps (blocks multiple FGFs) Phase I Fibroblast Growth Factor Receptor Targeting Agents: 15

16. VEGF overexpression is common in breast cancer. Bevacizumab (Avastin; Genentech), a humanized monoclonal antibody against VEGF, was granted accelerated approval in the US for the first-line treatment of MBC in combination with Paclitaxel in 2008. 1 st generation tyrosine kinase inhibitor; which also targets VEGFR are shown in previous table. Selected additional VEGF-targeted therapies : Aflibercept or VEGF Trap is an antiangiogenic peptide-antibody fusion containing portions of human VEGF receptor 1 and 2. Vascular disrupting agents (eg, Ombrabulin; Sanofi-Aventis) another class of antiangiogenic therapy, are under clinical trials for MBC. Vascular Endothelial Growth Factor (VEGF) 16

17. PDGFR is expressed in most breast tumors. The individual PDGF chains have different affinities for the two receptors- PDGFR α & PDGFR β. PDGFR α has high affinity for PDGF -A, -B, and -C, whereas PDGFR β has high affinity for PDGF -B and – D. Induces angiogenesis by up-regulating VEGF production. 1 st generation TKs; which also targets PDGFR are shown in previous table. Platelet Derived Growth Factor (PDGFR) 17

18. SRCs are small proteins of 160 kDa non-receptor tyrosine kinase and include SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2) and SRC-3. SRC may play a significant role in tumor progression and spread . SRC interact receptor tyrosine kinases (e.g. HER family), integrins, steroid hormone receptors, including the estrogen receptor. Steroid Receptor Coactivators (SRC) Inhibitors: Agents Stages Regimen Dasatinib Phase I/II Fulvestrant and MK‑0646 Bosutinib Phase II Single Agent Saracatinib Phase II Vs Zoledronic Steroid Receptor Coactivators (SRCs) 18

19. mTOR is a member of the cellular mTOR/PI3K/Akt pathway. A high proportion of breast tumors exhibit constitu­tive activation of the mTOR pathway. Rapamycin is a macrolytic lactone produced by Streptomyces hygroscopicus , which has immunosuppressive, antimicrobial, and antitumor properties. Rapamycin targets a principal protein that was named mTOR. Two mTOR complexes have been identified: mTORC1 and mTORC2 of cell growth and proliferation, cell metabolism, angiogenesis, and apoptosis. New agents are being developed that can inhibit both mTORC1 and mTORC2. Mammalian Target of Rapamycin (mTOR) Phosphoinositide 3-kinase (PI3K) Three classes of PI3K enzymes, designated I to III, have been identified; members of PI3K class I have been implicated in the mTOR pathway PI3K can be key target that, if effectively inhibited, could improve outcomes. 19

20. The mTOR/PI3K/Akt pathway PI3K inhibitor 20

21. Drug Drug class Stage of development Sirolimus (Rapamycin) mTOR inhibitor Approved Everolimus (RAD001) mTOR inhibitor Approved in 2012 for postmenopausal women with advanced HR+/HER2- breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole Ridaforolimus (deforolimus) (AP23573) mTOR inhibitor Phase III clinical trials PP242 mTOR inhibitor Preclinical BN107 mTOR inhibitor Preclinical mTOR inhibitors: 21

22. Sirolimus (Rapamycin) Everolimus 22

23. PI3K selective inhibitors: Agents Company Stage PX-866 Oncothyreon Inc Phase I GDC-0941 Genentech Inc Phase II XL-147 Exelixis Phase I/II BKM-120 Novartis Phase I 23

24. Drug Drug class Stage of development PI-103 Dual kinase inhibitor Preclinical LY294002 Dual kinase inhibitor Preclinical NVP-BEZ235 Dual kinase inhibitor Phase I/II clinical trials SF1126 Dual kinase inhibitor Phase I/II XL765 Dual kinase inhibitor Phase I BGT226 Dual kinase inhibitor Phase I/II Dual kinase (mTOR &PI3K) inhibitors: 24

25. DNA damage, double strand breaks are highly toxic to cells Homologous recombination is DNA repair mechanism. Homologous recombination is dependent on functional BRCA 1 and 2 pathways. Germline mutations in either the BRCA1 or BRCA2 genes are associated with a high risk of developing a number of breast cancers. When the BRCA-associated DNA repair pathway (homologous recombination) – is lost or dysfunctional, repair shifts toward alternate DNA repair mechanisms dependent on a unique class of enzymes, Poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP). Poly-{Adenosine diphosphate (ADP)-Ribose} Polymerase (PARP) 25

26. PARP-inhibitors in clinical development: Agent Company Stages Olaparib (AZD2281) AstraZeneca/KuDOS Phase I/II Veliparib Abbott Phase I/II BS1-201 BiPar/SanofiAventis Phase II/III AG014699 Pfizer Phase I/II MK482 Merck Phase I INO-1001 Inotek Phase I CEP9272 Cephalon Phase I 26

27. Targeted cancer therapies hold the promise of being more selective, reducing side effects, and improving quality of life. Targeted therapies may work best in combination, either with other targeted therapies or with more traditional therapies. Researchers are working to find new ways to target cancer cells as part of treatment. Various targeted therapies are being studied in clinical trials to see how well they work in treating breast cancer. As more targets are identified and therapies are developed, doctors will be able to offer patients treatment that works best for their type of breast cancer . In future, metastatic breast cancer, triple negative breast cancer can be well treated. Conclusion 27

28. Thank You 28