Improving the Efficacy of PARP1 Inhibitors by Targeting the Tumor Stroma

Background & Unmet Need

• Poly (ADP-ribose) polymerase (PARP) inhibitors are a class of cancer drugs which are commonly used to treat BRCA1/2 mutant ovarian and breast cancers
• However, resistance to PARP1 inhibitors is common, with more than 40% of BRCA1/2 mutant patients not responding to therapy1
• The tumor microenvironment is implicated to be a driving factor of tumor progression and treatment resistance, and activation of cancer-associated fibroblasts (CAFs) can affect treatment outcomes
• P62 is a master regulator of CAF activation, and downregulation of p62 has been shown to promote CAF phenotype in tumor stroma
• However, the mechanism by which p62 is downregulated in tumors remains unclear
• Unmet Need: Methods of inhibiting the activation of the tumor microenvironment, especially CAFs, for improved therapeutic effect and duration

Technology Overview

• The Technology:Combination therapies to increase the effectiveness of PARP1 inhibitors by inhibiting activation of tumor stroma and CAFs
• The Discovery: PARP1 inhibitors generate a feedback loop that activates CAFs by downregulating master regulator p62
• Therefore, combination treatment with a PARP1 inhibitor and an inhibitor of stromal activation may revert stroma activation and enhance anti-tumor activity
• PoC Data: Treatment with a stroma-targeted hyaluronidase significantly enhanced olaparib antitumor activity both in vitro and in vivo models of prostate cancer
• This co-targeting mechanism is applicable in additional cancers such as lung, breast, and endometrium and for combinations of PARP1 and other stromal inhibitors, such as anti-TNFa, IL-6, and JAK molecules

Technology Applications

• Combination therapy of PARP1 inhibitor with drugs targeting TNFalpha, IL-6, or Janus kinase (JAK)
• Combination therapy of PARP1 inhibitors with other drugs that target the stroma, such as hyaluronan (HA) synthase inhibitors, fibroblast activation protein alpha (FAPα) inhibitors, SMO-inhibitors, CXCL12 antagonists, or DDR2 inhibitors

Technology Advantages

• Combination therapy improves efficacy of PARP1 inhibitor therapy
• May reduce refractory rates of treatment with PARP1 inhibitors

Figure 1: Schematic depicting how PARP inhibitors activate CAFs.