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Ref Type Journal Article
PMID (32499300)
Authors Perino S, Moreau B, Freda J, Cirello A, White BH, Quinn JM, Kriksciukaite K, Someshwar A, Romagnoli J, Robinson M, Movassaghian S, Cipriani T, Wooster R, Bilodeau MT, Whalen KA
Title Novel Miniaturized Drug Conjugate Leverages HSP90-driven Tumor Accumulation to Overcome PI3K Inhibitor Delivery Challenges to Solid Tumors.
Journal Molecular cancer therapeutics
Vol 19
Issue 8
Date 2020 08
URL
Abstract Text The PI3K pathway is considered a master regulator for cancer due to its frequent activation, making it an attractive target for pharmacologic intervention. While substantial efforts have been made to develop drugs targeting PI3K signaling, few drugs have been able to achieve the inhibition necessary for effective tumor control at tolerated doses. HSP90 is a chaperone protein that is overexpressed and activated in many tumors and as a consequence, small-molecule ligands of HSP90 are preferentially retained in tumors up to 20 times longer than in normal tissue. We hypothesize that the generation of conjugates that use a HSP90-targeting ligand and a payload such as copanlisib, may open the narrow therapeutic window of this and other PI3K inhibitors. In support of this hypothesis, we have generated a HSP90-PI3K drug conjugate, T-2143 and utilizing xenograft models, demonstrate rapid and sustained tumor accumulation of the conjugate, deep pathway inhibition, and superior efficacy than the PI3K inhibitor on its own. Selective delivery of T-2143 and the masking of the inhibitor active site was also able to mitigate a potentially dose-limiting side effect of copanlisib, hyperglycemia. These data demonstrate that by leveraging the preferential accumulation of HSP90-targeting ligands in tumors, we can selectively deliver a PI3K inhibitor leading to efficacy in multiple tumor models without hyperglycemia in mice. These data highlight a novel drug delivery strategy that allows for the potential opening of a narrow therapeutic window through specific tumor delivery of anticancer payloads and reduction of toxicity.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
T-2143 T2143|T 2143 T-2143 is an HSP90-PI3K drug conjugate, which selectively targets PI3K, potentially resulting in decreased tumor cell proliferation and reduced tumor growth (PMID: 32499300).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA E545K lung non-small cell carcinoma sensitive T-2143 Preclinical - Cell line xenograft Actionable In a preclinical study, T-2143 treatment reduced proliferation of non-small cell lung cancer cells harboring PIK3CA E545K in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 32499300). 32499300
PIK3CA H1047R colon cancer sensitive T-2143 Preclinical - Cell line xenograft Actionable In a preclinical study, T-2143 treatment inhibited Akt phosphorylation and proliferation of colon cancer cells harboring PIK3CA H1047R in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 32499300). 32499300