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Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug.

ABSTRACT: Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with ?? T cells expressing V?2?V?2 TCRs. Although treatment with ?? T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate ?? T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated ?? T cells to secrete TNF-? in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded ?? T cells and stimulated them to secrete interferon-? and kill tumor cells. In preclinical studies, combination therapy with compound 7 and ?? T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with ?? T cells.

SUBMITTER: Tanaka Y

PROVIDER: S-EPMC5519590 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug.

Tanaka Yoshimasa Y Iwasaki Masashi M Murata-Hirai Kaoru K Matsumoto Kenji K Hayashi Kosuke K Okamura Haruki H Sugie Tomoharu T Minato Nagahiro N Morita Craig T CT Toi Masakazu M

Scientific reports 20170720 1

Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodr ...[more]

PMID: 28729550

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Project description:AST-3424/OBI-3424 (denoted by 3424) is a novel prodrug bis-alkylating agent activated by AKR1C3. AKR1C3 is overexpressed in many types of cancer, particularly in liver, non-small cell lung, gastric, renal and CRPC cancer. Currently 3424 is being studied in phase 1/2 clinical trials for the treatment of solid and hematologic cancers, and it represents potentially a novel, selective anti-cancer agent for multiple indications. In this study, AKR1C3-dependent activation of 3424 was investigated in vitro using recombinant human AKR1C3. AKR1C3-dependent cytotoxicity of 3424 was determined in a wide range of human cancer cell lines with different AKR1C3 expression levels. In addition, anti-tumor activity of 3424 was also investigated in a broad panel of CDX and PDX models. AKR1C3-dependent activation of prodrug 3424 was evident by monitoring the decrease of 3424 and generation of the active form, 2660. Kinetic analysis indicated that AKR1C3 exhibited higher catalytic efficiency towards 3424 compared to the physiological substrates. There was a strong correlation between 3424 cytotoxic potency and AKR1C3 expression. The racemic mixture induced DNA cross-linking in a concentration dependent manner. Tumor growth inhibition of 3424 was shown to be better than or comparable to the standard of care chemotherapy at clinically achievable doses as a single agent in various CDX models with high expression of AKR1C3, including liver HepG2, lung H460, castration-resistant prostate VCaP, gastric SNU-16, and kidney A498 cancer cell lines. The excellent anti-tumor efficacy of 3424 was further demonstrated in PDX models which have high level of AKR1C3 expression, but not in a model with low level of AKR1C3 expression. In the combination therapy, we showed that 3424 could enhance the efficacy of the standard care of chemotherapy in the CDX models. The results described here highlight that 3424 exhibits AKR1C3-dependent cytotoxicity in vitro and anti-tumor activity in vivo in a wide range of human cancer types, which support further development of 3424 as an anti-cancer agent for treating different types of cancers and the use of AKR1C3 as a biomarker to profile cancer patients and further guide patient selection for therapy with 3424.

Dataset Information

Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug.

Publications

Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug.

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