BERKELEY, CA (UroToday.com) - Bladder cancer is the second most common malignancy of the urinary tract and the fourth most frequent cancer in men in developed countries. At initial diagnosis, non muscle-invasive bladder cancer (NMIBC) accounts for 70% of patients and muscle-invasive bladder cancer (MIBC) the remaining 30%. NMIBC has a high probability for relapse, ranging from 31% to 78% within 5 years. A more serious challenge for these patients is progression rates up to 45% for high-risk disease (Babuk et al., 2011, Eur Urol, 64(4):639) (Shelly et al., 2010, Cancer Treat Rev, 36(3):195). To address these challenges, various regimes of intravesical chemotherapies including mitomycin-c (MMC) have been developed. MMC alkylates and cross-links DNA, thereby inducing DNA damage-response systems including DNA repair. This may circumvent the intended chemotherapeutic effect. Bladder tumors showing increased expression of DNA repair proteins respond poorly to chemotherapy (Li et al., 2012, Med Sci Monit, 18(4):BF156), and somatic mutations in DNA repair genes are found to be favorable prognostic markers for recurrence-free survival (Yap et al., 2014, Clin Cancer Res, 20(24):6605). Therefore, protein components of the DNA damage response (DDR) systems are promising targets for cancer therapy.
In this paper, a cell penetrating peptide (ATX-101) containing the novel PCNA interacting motif APIM (Gilljam et al., 2009, J Cell Biol, 186(5):645) sensitizes bladder cancer cells to chemotherapeutics, including MMC. The hypersensitivity of the cancer cells is due to ATX-101´s ability to impair the PCNA interaction of several different DNA damage response proteins, including several DNA repair proteins. ATX-101 blocks the “stress switch” of the cells which is more detrimental for deregulated cancer cells than normal cells, see illustration of mode of action.
ATX-101 has previously been shown to efficiently penetrate cells and to have strong anti-cancer activities in preclinical multiple myeloma models (Müller et al., 2013, PLos One, 8(7):270430). This paper shows that ATX-101 efficiently penetrated the bladder wall, down to the muscle layer, after intravesical instillation. The peptide increased the efficacy of MMC also in slow growing endogenous cancers. Furthermore, PCNA levels in cancer cells are not a prognostic factor for sensitivity to the combinatory effect.
Limited progress has been made in bladder cancer therapy the last thirty years and this is reflected in minimal targeted therapy for these patients. This paper provides new and important information about PCNA´s vital role in regulation of cellular stress responses and the importance of the APIM binding sequence. Understanding how PCNA regulates genome stability is a “hot topic” because these processes are potential intervention points in cancer treatment. APIM-peptides are promising as adjuvant drug for various treatment regimens, not just NMIBC but also for a broad variety of other cancers (including MIBC).
The NTNU spin-off company APIM Therapeutics AS (www.apimtherapeutics.com), where Professor Marit Otterlei is inventor and founder, is developing the APIM-peptide ATX-101 for use in cancer therapy. GLP-toxicology studies are ongoing and a phase I/IIa clinical trial for NMIBC (marked lesion) is planned for 2016.
Carl-Jørgen Arum, MD, PhDa and Marit Otterlei, PhDb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aCarl-Jørgen Arum, MD, PhD, Asst. Professor, Department of Cancer Research and Molecular Medicine, NTNU / St. Olav's Hospital, Trondheim University Hospital, Trondheim Norway
bProfessor, Department of Cancer Research and Molecular Medicine, NTNU / CSO APIM Therapeutics AS, Trondheim Norway