Therapeutic Windows

Targeting Replication protein A (Rpa) as an anti-cancer therapy

01.07.2015 bis 30.06.2018

In contrast to hematopoietic malignancies, molecular therapies in major solid tumors are limited due to an inevitable development of therapy resistance. A prototype of a therapy resistant solid is Hepatocellular carcinoma (HCC), a tumor that represents a major health problem with more than 700.000 deaths worldwide and very limited treatment options. HCC shows a general resistance against cytotoxic agents (Yau et al., 2008) and only recently the kinase inhibitor Sorafenib was approved as the first systemic treatment of HCC patients, however, Sorafenib prolongs life of patients with advanced HCC by only 2.8 months in average (Wilhelm et al., 2006). We hypothesize that essential cellular processes might represent promising therapeutic targets to overcome therapy resistance of HCC and other solid tumors.
When targeting an essential cellular process for cancer therapy, , a therapeutic window might occur either because inhibition of an essential processes induces a stress response specifically or predominantly in cancer cells but not in normal cells or because the respective cellular process is upregulated in cancer cells resulting in a higher dependency on the process in cancer- vs. normal cells. Since the replicative potential of tumor cells is strongly dependent on DNA metabolism, proteins involved in these essential processes may represent vulnerabilities which can be exploited therapeutically. The fact that non-cancerous cells mostly exhibit a lower proliferation rate than tumor cells is likely to contzribute to a therapeutic window allowing to exploiting DNA replication as a target for cancer therapy.
Due to its important role in DNA metabolism, we hypothesized that Replication protein A (Rpa) might represent a promising target in HCC and other therapy resistant solid tumors. Rpa is the major single-stranded DNA binding protein and is needed for all major intermediate steps of single-stranded genomic DNA in DNA replication, DNA repair, DNA recombination, telomere maintenance and induction of DNA damage checkpoints [reviewed in (Zou et al., 2006)]. Rpa is a heterotrimer protein complex composed of three subunits: Rpa1 (also known as Rpa70), Rpa2 (also known as Rpa32) and Rpa3 (also known as Rpa14). Whereas Rpa1 is the main DNA binding subunit, Rpa2 plays a major role in regulation of Rpa downstream targets and contains a N-terminal phosphorylation domain. Rpa3 was shown to be important for the formation of the Rpa complex and hence shRNA mediated knockdown of Rpa3 destabilizes the whole Rpa complex (McJunkin et al., 2011).