Targeted agents in Targeted agents in Gynecologic Cancer Gynecologic Cancer Amit M Oza Amit M Oza Amit M. Oza Amit M. Oza Professor of Medicine, Professor of Medicine, Princess Margaret Hospital, Princess Margaret Hospital, University of Toronto University of Toronto y Co Co- -Chair Gynecology, NCIC CTG Chair Gynecology, NCIC CTG
Targeted Therapies Targeted Therapies Targeted Therapies Targeted Therapies Incorporation of novel targeted therapies Incorporation of novel targeted therapies Incorporation of novel targeted therapies Incorporation of novel targeted therapies � Biologic rationale Biologic rationale � Prevalence of target Prevalence of target Prevalence of target Prevalence of target � Characteristics of the target Characteristics of the target Amenable to modulation Amenable to modulation � Availability of inhibitor Availability of inhibitor � Effect of target inhibition in patients Effect of target inhibition in patients – – activity activity of inhibitors of inhibitors f i hibit f i hibit
Therapies for intracellular targets Therapies for intracellular targets Therapies for intracellular targets Therapies for intracellular targets Virt e of promisc it o er fidelit ? Virt e of promisc it o er fidelit ? Virtue of promiscuity over fidelity? Virtue of promiscuity over fidelity? � Complexity of signal transduction pathways Complexity of signal transduction pathways � value of single target � value of single target value of single target value of single target Combined approaches due to synergy Combined approaches due to synergy � Eg target EGFR + Chemo � Eg target EGFR + Chemo Eg target EGFR + Chemo Eg target EGFR + Chemo � Sequential or concurrent therapy Sequential or concurrent therapy � Combinations of targeted agents Combinations of targeted agents g g g g Aberrations in multiple inter Aberrations in multiple inter- -related pathways related pathways � Develop clinical and translational studies Develop clinical and translational studies
Molecular Pathways of Interest Molecular Pathways of Interest Molecular Pathways of Interest Molecular Pathways of Interest Angiogenesis Angiogenesis – g g g g � Ovarian, Endometrial, Cervical Ovarian, Endometrial, Cervical � PI3 Kinase PI3 Kinase – – AKT AKT – – mTOR mTOR - - � Endometrial, Ovarian Endometrial Ovarian Endometrial Ovarian Endometrial, Ovarian � Epigenetic mechanisms Epigenetic mechanisms – – � Ovarian, Endometrial Ovarian, Endometrial � EGFR targeting EGFR targeting � Ovarian, Cervical, endometrial Ovarian, Cervical, endometrial � Poly (ADP Poly (ADP-ribose) polymerase inhibition (parp Poly (ADP ribose) polymerase inhibition (parp Poly (ADP ribose) polymerase inhibition (parp ribose) polymerase inhibition (parp inhibition) inhibition) – – � Ovarian Ovarian �
Faivre et al Nature Reviews Drug Discovery 5 671–688 (August 2006) | doi:10 1038/nrd2062 Faivre et al. Nature Reviews Drug Discovery 5 , 671 688 (August 2006) | doi:10.1038/nrd2062
Rationale Rationale for for Anti Anti- -angiogenic angiogenic therapy therapy As tumours increase in size, become dependent , p on vasculature Exploitable differences between normal and tumour vasculature l Affecting one blood vessel effects large numbers of tumour cells of tumour cells Endothelial cells are less likely to develop drug resistance due to slower rates of division es sta ce due to s o e ates o d s o May actually be synergistic with cytotoxic May actually be synergistic with cytotoxic chemotherapy and radiotherapy chemotherapy and radiotherapy
The Angiogenic Switch and The Angiogenic Switch and Antiangiogenic Therapy Antiangiogenic Therapy Antiangiogenic Therapy Antiangiogenic Therapy Tumor secretion of Small Angiogenic inhibitors Somatic angiogenic factors Rapid tumor growth and avascular may reverse this mutation stimulates metastasis tumor vascularization angiogenesis Carmeliet and Jain. Nature . 2000;407:249.
Angiogenesis is involved throughout tumour Angiogenesis is involved throughout tumour Angiogenesis is involved throughout tumour Angiogenesis is involved throughout tumour formation, growth and metastasis formation, growth and metastasis Premalignant Malignant Tumour Vascular Dormant Overt stage tumour growth invasion micrometastasis metastasis (Avascular (Angiogenic (Vascularised (Tumour cell (Seeding in (Secondary (S o da y tumour) switch) tumour) intravasation) distant organs) angiogenesis) Stages at which angiogenesis plays a role in tumour progression g g g p y p g Adapted from Poon RT-P , et al. J Clin Oncol 2001;19:1207–25
Tumour vasculature differs Tumour vasculature differs from normal vasculature from normal vasculature Normal blood vessels Normal blood vessels Tumour blood vessels Normal blood vessels Normal blood vessels Tumour blood vessels Tumour blood vessels Tumour blood vessels Growth factors (VEGF) Maturation factors N No growth factors th f t Integrins Tight Fewer supporting cells Leaky Support cells Jain R. Nat Med 2003;9:685–93 Carmeliet P . Nat Med 2003;9:653–60
Key mediator of Key mediator of VEGF VEGF angiogenesis angiogenesis angiogenesis angiogenesis Controls tumour growth by Controls tumour growth by Stimulating tumour Stimulating tumour angiogenesis angiogenesis Maintaining tumour vasculature Maintaining tumour vasculature Increasing Increasing vascular vascular permeability permeability Affecting the normal immune Affecting the normal immune response response p Possible direct effect on tumour Possible direct effect on tumour cells cells Ovarian cancer : Ovarian cancer : High VEGF secretion and expression High VEGF secretion and expression � Latter related to stage/mitotic activity Latter related to stage/mitotic activity - - prognosis prognosis � VEGF angiogenic and permeability factor: ascites VEGF angiogenic and permeability factor: ascites
VEGF VEGF VEGF VEGF Normal Key mediator of Key mediator of angiogenesis angiogenesis � Stimulating tumour angiogenesis Proliferation and migration of � endothelial cells endothelial cells Maintaining tumour vasculature Survival of endothelial cells � Increasing vascular permeability Cancer Increases interstitial fluid � pressure Impairs delivery of O 2, , 2, nutrients and drugs Hypoxic loop set up causing further production of VEGF May allow tumour cells to enter – the circulation and metastasize Konerding et al BJC 1999, 80; 724-32
Agents Targeting the Agents Targeting the Agents Targeting the VEGF Agents Targeting the VEGF VEGF VEGF Pathway Pathway Antibodies inhibiting Soluble VEGF receptors VEGF receptors (VEGF-TRAP) Antibodies inhibiting VEGF (e.g. bevacizumab) ↑ Permeability VEGF Cation VEGF channel receptor-2 Small-molecules P– – P – P – P P– inhibiting VEGF receptors P– – P P– P– (TKIs) P– – P – P (e.g. PTK-787) Migration, permeability, DNA synthesis, survival Ribozymes (Angiozyme) A Angiogenesis i i L Lymphangiogenesis h i i
Single Agent Bevacizumab Single Agent Bevacizumab in Ovarian Cancer in Ovarian Cancer GOG 170D GOG 170D (Burger ASCO 2005) (Burger ASCO 2005) Cannistra et al Cannistra et al (ASCO 2006) (ASCO 2006) Bevacizumab 15mg/kg q 3/52 Bevacizumab 15mg/kg q 3/52 Bevacizumab 15mg/kg q 3/52 Bevacizumab 15mg/kg q 3/52 N=64 N=64 N=44 N=44 1 or 2 previous chemotherapy 1 or 2 previous chemotherapy Up to 3 prior chemotherapy courses, Up to 3 prior chemotherapy courses, courses, 55% platinum resistant courses, 55% platinum resistant 100% platinum resistant 100% platinum resistant RR 18% (CR 5%) SD 55% RR 18% (CR 5%) SD 55% RR 16% (CR 0%) SD 25% RR 16% (CR 0%) SD 25% 6month PFS 38.7% 6month PFS 38.7% 6 month PFS 27% 6 month PFS 27% Median PFS 4.7months Median PFS 4.7months Median PFS 4.3months Median PFS 4.3months Median OS 17months Median OS 17months Median OS not reached Median OS not reached SE: Emesis, constipation, TE SE: Emesis, constipation, TE SE: Arterial TE, GI perforation, HT SE: Arterial TE, GI perforation, HT
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