Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Mutation in the tumor suppressor gene TP53 is an early event in the development of high-grade serous (HGS) ovarian cancer and is identified in more than 96 % of HGS cancer patients. APR-246 (PRIMA-1 ^MET) is the first clinical-stage compound that reactivates mutant p53 protein by refolding it to wild type conformation, thus inducing apoptosis. APR-246 has been tested as monotherapy in a Phase I/IIa clinical study in hematological malignancies and prostate cancer with promising results, and a Phase Ib/II study in combination with platinum-based therapy in ovarian cancer is ongoing. In the present study, we investigated the anticancer effects of APR-246 in combination with conventional chemotherapy in primary cancer cells isolated from ascitic fluid from 10 ovarian, fallopian tube, or peritoneal cancer patients, 8 of which had HGS cancer.

Methods

Cell viability was assessed with fluorometric microculture cytotoxicity assay (FMCA) and Combination Index was calculated using the Additive model. p53 status was determined by Sanger sequencing and single strand conformation analysis, and p53 protein expression by western blotting .

Results

We observed strong synergy with APR-246 and cisplatin in all tumor samples carrying a TP53 missense mutation, while synergistic or additive effects were found in cells with wild type or TP53 nonsense mutations. Strong synergy was also observed with carboplatin or doxorubicin. Moreover, APR-246 sensitized TP53 mutant primary ovarian cancer cells, isolated from a clinically platinum-resistant patient, to cisplatin; the IC ₅₀ value of cisplatin decreased 3.6 fold from 6.5 to 1.8 μM in the presence of clinically relevant concentration of APR-246.

Conclusion

These results suggest that combination treatment with APR-246 and DNA-damaging drugs could significantly improve the treatment of patients with TP53 mutant HGS cancer, and thus provide strong support for the ongoing clinical study with APR-246 in combination with carboplatin and pegylated liposomal doxorubicin in patients with recurrent HGS cancer.

Related collections

Most cited references 23

Record: found
Abstract: found
Article: found

Is Open Access

Role of Glutathione in Cancer Progression and Chemoresistance

Nicola Traverso, Roberta Ricciarelli, Mariapaola Nitti … (2013)

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.

0 comments Cited 347 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer.

D Ali, V Bykov, Gunnar Juliusson … (2012)

APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246. APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg. MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response. We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.

0 comments Cited 163 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Are all pelvic (nonuterine) serous carcinomas of tubal origin?

Robert Kurman, Chris G Przybycin, Russell Vang … (2010)

It has been proposed that the presence of tubal intraepithelial carcinoma (TIC), in association with one-third to nearly half of pelvic serous carcinomas, is evidence of fallopian tube origin for high-grade serous carcinomas that would have been otherwise classified as primary ovarian or peritoneal. To address this hypothesis, we evaluated a series of 114 consecutive pelvic (nonuterine) gynecologic carcinomas at our institution (2006 to 2008) to determine the frequency of TIC in 52 cases in which all the resected fallopian tube tissue was examined microscopically. These 52 cases were classified as ovarian (n=37), peritoneal (n=8), or fallopian tube (n=7) in origin as per conventional criteria based on disease distribution. The presence of TIC and its location and relationship to invasive carcinoma in the fallopian tubes and ovaries were assessed. Among the 45 cases of ovarian/peritoneal origin, carcinoma subtypes included 41 high-grade serous, 1 endometrioid, 1 mucinous, 1 high-grade, not otherwise specified, and 1 malignant mesodermal mixed tumor. TIC was identified in 24 cases (59%) of high-grade serous carcinoma but not among any of the other subtypes; therefore, the term serous TIC (STIC) is a more specific appellation. STICs were located in the fimbriated end of the tube in 22 cases (92%) and in the ampulla in 2 (8%); they were unilateral in 21 (88%) and bilateral in 3 (13%). STICs in the absence of an associated invasive carcinoma in the same tube were detected in 7 cases (30%) and with invasive carcinoma in the same tube in 17 (71%). Unilateral STICs were associated with bilateral ovarian involvement in 15 cases and unilateral (ipsilateral) ovarian involvement in 5 (the remaining case with a unilateral STIC had a primary peritoneal tumor with no ovarian involvement); the bilateral STICs were all associated with bilateral ovarian involvement. Six of the 7 primary tubal tumors were high-grade serous carcinomas, and 4 of these 6 (67%) had STICs. Based on conventional criteria, 70%, 17%, and 13% of high-grade serous carcinomas qualified for classification as ovarian, peritoneal, and tubal in origin, respectively; however, using STIC as a supplemental criterion to define a case as tubal in origin, the distribution was modified to 28%, 8%, and 64%, respectively. Features of tumors in the ovary that generally suggest metastatic disease (bilaterality, small size, nodular growth pattern, and surface plaques) were identified with similar frequency in cases with and without STIC and were, therefore, not predictive of tubal origin. The findings, showing that nearly 60% of high-grade pelvic (nonuterine) serous carcinomas are associated with STICs, are consistent with the proposal that the fallopian tube is the source of a majority of these tumors. If these findings can be validated by molecular studies that definitively establish that STIC is the earliest form of carcinoma rather than intraepithelial spread from adjacent invasive serous carcinoma of ovarian or peritoneal origin, they will have important clinical implications for screening, treatment, and prevention.

0 comments Cited 107 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Nina Mohell: nina.mohell@aprea.com

Journal

Journal ID (nlm-ta): J Ovarian Res

Journal ID (iso-abbrev): J Ovarian Res

Title: Journal of Ovarian Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-2215

Publication date (Electronic): 14 May 2016

Publication date PMC-release: 14 May 2016

Publication date Collection: 2016

Volume: 9

Electronic Location Identifier: 27

Affiliations

[ ]Aprea AB, Solna, Sweden

[ ]Karolinska University Hospital, Stockholm, Sweden

[ ]Karolinska Institutet Dept. of Oncology-Pathology, Cancer Center Karolinska (CCK), Stockholm, Sweden

Article

Publisher ID: 239

DOI: 10.1186/s13048-016-0239-6

PMC ID: 4868029

PubMed ID: 27179933

SO-VID: b6661846-f963-486d-83ac-83c7d092b3c6

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 February 2016

Date accepted : 5 May 2016

Funding

Funded by: the Swedish Cancer Society

Award ID: 130260

Award ID: 140616

Award Recipient : Svetlana Bajalica-Lagercrantz

Custom metadata

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: ovarian cancer,high-grade serous (hgs) cancer,apr-246 (prima-1met),primary cancer cells,tp53 mutation,p53 reactivation,dna-damaging drugs,cisplatin,doxorubicin,synergy

Data availability:

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: ovarian cancer, high-grade serous (hgs) cancer, apr-246 (prima-1met), primary cancer cells, tp53 mutation, p53 reactivation, dna-damaging drugs, cisplatin, doxorubicin, synergy

Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer

Read this article at

Abstract

Background

Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 23

Role of Glutathione in Cancer Progression and Chemoresistance

Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer.

Are all pelvic (nonuterine) serous carcinomas of tubal origin?

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 171

Cited by 34

Most referenced authors 729