Targeting Cancer Vulnerabilities Through RNA Splicing: Cancer Research UK Funds Early Development of ORIC-259

When cancer develops resistance to PARP inhibitors, finding another vulnerability that could deprive tumors of their survival advantage becomes an important focus of treatment development. The oral small-molecule drug candidate ORIC-259 targets CIP2A, a protein in cancer cells that is difficult to target directly with drugs: it aims to alter the RNA message used to make this protein, reducing protein production at its source.

ORIC Pharmaceuticals announced on October 5 that it had signed an agreement with Cancer Research UK, whose Centre for Drug Development will fully fund, sponsor, design and conduct the preparatory studies required for a clinical trial application and a Phase 1/2 trial. Cancer Research Horizons also confirmed the collaboration the following day, explaining that the trial will assess safety, tolerability and preliminary antitumor activity. This is an arrangement to advance human studies, not an announcement that trial enrollment has begun.

CIP2A is involved in signaling regulation, cell division and the DNA damage response in cancer cells. According to ORIC, ORIC-259 alters RNA splicing so that the message contains a signal to stop protein production prematurely, leading to degradation of that messenger RNA and a reduction in CIP2A protein. This approach uses a small molecule to intervene in the cell’s existing RNA processing machinery, offering another development path for proteins that are difficult to inhibit directly.

This approach is particularly aimed at cancers with homologous recombination deficiency (HRD). Cancer Research Horizons noted that research has identified a “synthetic lethal” vulnerability involving CIP2A in BRCA-mutated cancers: cancer cells’ existing repair defects may make them more dependent on another survival function, and blocking that function as well could make it difficult for them to survive. However, whether this biological finding can translate into a treatment that patients can tolerate and that is effective still requires human data.

ORIC said that preclinical studies observed antitumor activity in both PARP inhibitor-sensitive and PARP inhibitor-resistant settings. The collaborators therefore suggested that ORIC-259 could potentially be used after resistance to PARP inhibitors develops, and that combinations with PARP inhibitors or other drugs could also be explored. These remain directions to be validated; the announcement did not provide complete details on models, doses and data sufficient for an independent assessment of the effects, nor did it include patient efficacy results.

The collaboration also sets out arrangements for subsequent rights. ORIC retains an exclusive option to reacquire the rights to ORIC-259 after obtaining Phase 1/2 data, while Cancer Research UK is eligible to receive subsequent milestone payments and royalties, with the commercial relationship managed by Cancer Research Horizons. The parties did not disclose payment amounts; ORIC said this arrangement allows the company to concentrate its internal resources on its later-stage clinical pipeline.

The next key question is whether human trials can identify a dose that is safe, tolerable and shows a signal of antitumor activity. The announcement did not specify a trial start date, enrollment size or full eligibility criteria. For patients with BRCA-mutated and HRD cancers, the collaboration provides resources to advance a new treatment concept, but clinical research is still needed to demonstrate whether it can overcome resistance.