Clinical utility of targeted treatments in the management of epithelial ovarian cancer

Figures & data

Table 1 Key pathways involved in the pathogenesis of epithelial ovarian cancer

Pathway	Function
Angiogenesis	Formation of new blood vessels to support cancer growth and metastasis; involved in vascular permeability and vasodilation.
Epidermal growth factor receptor	Membrane receptors that dimerize and activate tyrosine kinase activity, leading to activation of MAPK and PI3K/AKT pathways. This leads to increased cell growth and decreased apoptosis.
Folate pathway	Essential for purine biosynthesis; folate transporter overexpression increases folate to cancer cells, leading to DNA replication and tumor growth.
Polyadenosine diphosphate-ribose polymerase	Enzyme that repairs DNA single-strand breaks via base excision repair pathway. Inhibition of pathway leads to increased single-strand breaks, and thus DNA double-strand breaks. BRCA mutations lead to defective double-strand break repairs, resulting in chromosome instability and cell death.
PI3K-AKT-mTOR pathway	Regulates apoptosis, metabolism, cell proliferation, angiogenesis, and cell growth.

Abbreviations: PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; MAPK, mitogen activated protein kinase.

Table 2 Summary of current clinical trials of targeted therapies for recurrent ovarian cancer*

Class	Drug	Intervention	Phase	Protocol ID
Angiogenesis inhibitors	Bevacizumab	Paclitaxel-topotecan-doxorubicin Paclitaxel-topotecan-doxorubicin, bevacizumab	III	MO22224, 2009-011400-33, NCT00976911
	Bevacizumab	Carboplatin, paclitaxel, bevacizumab	III	MO22923, 2010-019525-34, NCT01239732
	Bevacizumab	Carboplatin, bevacizumab	II	2008-000878-20, S-20080033, 2612-3754, NCT00744718
	Bevacizumab	Bevacizumab, gemcitabine	II	AVF4314S, NCT01131039
	Bevacizumab, sorafenib (VEGF inhibitor)	Bevacizumab, sorafenib	II	070058, 07-C-0058, NCI-07-C-0058, NCI-P6840, 7358, NCT00436215
	Sorafenib	Sorafenib and topotecan	II	TRIAS 2009, NCT01047891
	AMG 386	Paclitaxel plus AMG 386 Paclitaxel plus placebo	III	TRINOVA1: 20090508, NCT01204749
	AMG 386	Doxorubicin or topotecan and AMG 386	I	20070182, NCT00770536
	BIBF 1120	Carboplatin, doxorubicin, BIBF 1120 in dose escalation	I	1199.119, 2010-022523-30, NCT01314105
	BIBF 1120	Doxorubicin, BIBF 1120 in dose escalation	I, II	GYN10-149, NCT01485874
	BIBF 1120	Carboplatin, doxorubicin, BIBF 1120	I	11990117, NCT01329549
	Pazopanib	Paclitaxel, pazopanib Paclitaxel, placebo	II	GOG-0186J, NCT01468909
	Pazopanib	Pazopanib	II	GEICO-1002, 2010-020439-38, NCT01262014
	Pazopanib	Doxorubicin, pazopanib in dose escalation	I, II	SCRI GYN 26, NCT01035658
	Pazopanib	Pazopanib and cyclophosphamide	I, II	3107000, NCT01238770
	Pazopanib	Carboplatin, paclitaxel, pazopanib in dose escalation	I, II	CDR0000703686, EORTC-55092, EU-21119, EUDRACT-2010-024077-39, NCT01402271
	Cediranib Olaparib	Cediranib and olaparib Olaparib only	I, II	DFCI 09-293, U01CA062490-16S2, NCI 8348, NCT01116648
Vascular disrupting agents	Ombrabulin	Ombrabulin Placebo	II	EFC10260, 2010-024631-16, U1111-1118-5437, NCT01332656
	Fosbretabulin	Bevacizumab, fosbretabulin Bevacizumab alone	II	GOG-01861, NCT01305213
	EP-100	1EP-100, paclitaxel Paclitaxel alone	II	ACT12601, U1111-1124-2062, NCT01485848
PARP inhibitors	AZD2281	Carboplatin AZD2281 in dose escalation	I	080092, 08-C-0092, NCT01445418
	Veliparib	Carboplatin, doxorubicin, veliparib in dose escalation	I	GOG-9927, NCT01459380
	Veliparib	Doxorubicin, veliparib in dose escalation	I	CDR0000674917, AECM-000248, 00-0248, 8475, NCT01145430
	Veliparib (ABT-888)	ABT-888 in dose escalation	I	UPCI 08-121, 8282, NCT00892736, CINJ-050810
	Veliparib (ABT-888)	Cyclophosphamide, ABT-888	II	110080, 11-C-0080, NCT01306032
	Veliparib	Veliparib	I, II	Veli-BRCA, NCT01472783
	Veliparib (ABT-888)	Topotecan and ABT-888 in dose escalation	I, II	MAYO-MC0861, MC0861, 8329, NCT01012817
	Iniparib (BSI-201)	Carboplatin, gemcitabine, iniparib	II	TCD11504, 20090208, NCT01033292
P13K/AKT/mTOR inhibitors	MK-2206	MK-2206	II	10-402, NCT01283035
	MM-121	Paclitaxel, MM-121 Paclitaxel alone	II	MM-121-04-02-08 (ARD11586), NCT01447706
	Temsirolimus	Temsirolimus and bevacizumab	II	MAYO-MC0845, MC0845, 8233, NCT01010126
	Everolimus	Carboplatin, doxorubicin, everolimus in dose escalation	I	IRB 10-019, NCI-2011-00055, NCT01281514
	Everolimus RAD001	RAD001 and bevacizumab	II	09-01-RAD001BEV, NCT01031381
	Everolimus	Bevacizumab Everolimus, bevacizumab	II	GOG-0186G, NCT00886691
Folate pathway inhibitors	Pralatrexate	Carboplatin and pralatrexate in dose escalation	I, II	10-113, NCT01188876
	Pemetrexed	Pemetrexed and carboplatin	II	MMC-08-04-097, NCT01001910
	Farletuzumab	Carboplatin, taxane, farletuzumab	III	MORAb003-004, NCT00849667
	MORAb-003	Carboplatin, taxane only
EGFR inhibitor	Panitumumab	Carboplatin, doxorubicin, panitumumab Carboplatin, doxorubicin	II	GMIHO-008/2009_AG56, 2010-018849-59, AG56, NCT01388621
	Panitumumab	Panitumumab and gemcitabine	II	WIH 20050782, NCT01296035

Note:

* Data for table obtained from http://www.cancer.gov/clinicaltrials and was accessed on February 9, 2012.

Abbreviations: VEGF, vascular endothelial growth factor; PARP, polyadenosine ribose pathway.

Table 3 Summary of current clinical trials of first-line targeted therapies for ovarian cancer*

Class	Drug	Intervention	Phase	Protocol ID
Angiogenesis inhibitors	Bevacizumab	Carboplatin, bevacizumab, paclitaxel in dose escalation	I	2010C0049, OSU 09149, NCT01219777
	Bevacizumab	IP carboplatin, IV paclitaxel, IV bevacizumab in dose escalation	I	2010CO062, OSU09115, NCT 01220154
	Bevacizumab	Standard chemotherapy plus bevacizumab for 30 months Standard chemotherapy plus bevacizumab for 15 months	III	AGO-OVAR 17, NCT01462890
	Bevacizumab	Carboplatin, paclitaxel, bevacizumab	II	2009-0186, NCT01097746
	AMG 386	Carboplatin, paclitaxel, AMG 386 Carboplatin, paclitaxel, placebo	III	TRINOVA3: 20101129/ENGOT-ov2, NCT01493505
PARP inhibitors	Veliparib	IV carboplatin, paclitaxel, bevacizumab, veliparib IP cisplatin IV/IP paclitaxel, bevacizumab, veliparib	I	GOG-9923, NCT00989651
	ABT-767	ABT-767 dose escalation study	I	M10-976, 2010-020795-37, NCT01339650
PI3K/mTOR inhibitor	BKM120	BKM120 once daily	II	11-211, NCT01501604
	Temsirolimus	Carboplatin, paclitaxel, temsirolimus ≥ temsirolimus consolidation	II	GOG-0268, NCT01196429

Note:

* Data for table obtained from http://www.cancer.gov/clinicaltrials and was accessed February 9, 2012.

Abbreviations: IV, intravenous; IP, intraperitoneal; PARP, polyadenosine ribose pathway; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin.