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Ref Type

Journal Article

PMID

(22693356)

Authors

Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, Atoyan R, Qu H, Yin L, Samson M, Zifcak B, Ma AW, DellaRocca S, Borek M, Zhai HX, Cai X, Voi M

Title

Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	18	15	2012 Aug 01	4104-13	Clin Cancer Res

URL

Abstract Text

Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells.We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action.CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells.CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CUDC-907	CUDC-907	5	6

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CUDC-907		Fimepinostat	HDAC Inhibitor 45 PI3K Inhibitor (Pan) 42	CUDC-907 (fimepinostat) is a dual PI3K and HDAC inhibitor, which prevents activation of the PI3K-AKT-mTOR signal transduction pathway, inhibits tumor cell growth, and promotes apoptosis in cancer cells (PMID: 22693356, PMID: 32459381).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA mutant	Advanced Solid Tumor	sensitive	CUDC-907	Preclinical - Cell line xenograft	Actionable	In a preclinical study, CUDC-907 inhibited PIK3CA, blocked downstream AKT pathway activation, and induced apoptosis and cell cycle arrest in both PIK3CA wild-type and PIK3CA mutant human cancer cell lines and xenograft models of multiple tumor types (PMID: 22693356).	22693356
PIK3CA mutant	hematologic cancer	sensitive	CUDC-907	Preclinical - Cell line xenograft	Actionable	In a preclinical study, CUDC-907 inhibited PIK3CA, blocked downstream AKT pathway activation, and induced apoptosis and cell cycle arrest in both PIK3CA wild-type and PIK3CA mutant human cancer cell lines and xenograft models of multiple solid and hematologic cancers (PMID: 22693356).	22693356
PTEN del	breast cancer	sensitive	CUDC-907	Preclinical - Cell culture	Actionable	In a preclinical study, CUDC-907 inhibited growth of breast cancer cells lines harboring Pten mutations and/or deletions (PMID: 22693356).	22693356
PTEN mutant	breast cancer	sensitive	CUDC-907	Preclinical - Cell culture	Actionable	In a preclinical study, CUDC-907 inhibited growth of breast cancer cells lines harboring Pten mutations and/or deletions (PMID: 22693356).	22693356
PIK3CA mutant	breast cancer	sensitive	CUDC-907	Preclinical	Actionable	In a preclinical study, CUDC-907 inhibited growth of human breast cancer cell lines harboring PIK3CA mutations in culture (PMID: 22693356).	22693356
PTEN del	prostate cancer	sensitive	Pictilisib + Vorinostat	Preclinical	Actionable	In a preclinical study, GDC-0941 and Zolinza (vorinostat) acted synergistically to inhibit growth of a human prostate cancer cell line harboring a PTEN deletion in culture (PMID: 9661880, PMID: 22693356).	22693356 9661880

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