Onconova Therapeutics' Preclinical Narazaciclib Data At SABCS Highlights Differentiated Anti-Tumor Activity v. Other CDK4/6i's

Author: Benzinga Newsdesk | December 08, 2023 05:05pm

Differentiated profile of narazaciclib supported by positive results of studies demonstrating broad multi-kinase activity, with significant anti-tumor activity and increased anti-tumor immunity, compared to approved CDK4/6 inhibitors

 

Data support the potential use of narazaciclib in breast and ovarian cancers

Narazaciclib progressing towards RP2D and preparation for registrational studies, with a planned update in H1 2024

NEWTOWN, Pa., Dec. 08, 2023 (GLOBE NEWSWIRE) -- Onconova Therapeutics, Inc. (NASDAQ:ONTX), ("Onconova" or "the Company"), a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer, today announced preclinical data highlighting narazaciclib's multi-kinase profile, broad anti-tumor activity and increased anti-tumor immunity, compared to palbociclib and other CDK4/6 inhibitors, in a poster presented at the San Antonio Breast Cancer Symposium (SABCS) on December 8, 2023.

"We are very pleased to share new data characterizing narazaciclib's differentiated activity, compared to palbociclib and other CDK4/6 inhibitors, especially in breast and ovarian cell lines, in a poster presentation at this year's San Antonio Breast Cancer Symposium (SABCS 2023)," said Steve Fruchtman, M.D., President and Chief Executive Officer.

Dr. Fruchtman continued, "Narazaciclib impacts a wider array of kinase targets and produced a more substantial reduction in cell viability across several large panels of breast and ovarian cell lines carrying a range of mutations, compared to palbociclib. In addition, narazaciclib treatment induced higher levels of T-cell recruiting chemokines, supporting greater anti-tumor immune activity."

"We believe that the totality of the data presented at SABCS supports narazaciclib's multi-kinase activity, its ability to target resistance pathways missed by other CDK4/6 inhibitors, and its differentiated anti-tumor and immunomodulatory activity. We hope to further demonstrate the promise of narazaciclib's differentiated profile in patients as we progress the clinical program in 2024 towards the definition of a recommended Phase 2 dose (RP2D). We are also preparing to initiate pivotal studies in the lead indication of low grade endometrioid endometrial cancer (LGEEC), and to expand into investigator-sponsored studies in breast and ovarian cancers," concluded Dr. Fruchtman.

Poster Overview

Title: Narazaciclib's differential targets and kinase inhibitory activity compared to the approved CDK4/6 inhibitors (CDK4/6is) contribute to the enhanced inhibition of tumor growth in preclinical models

Objectives: To explore the activity of narazaciclib and its metabolite, ON1232580, in comparison to the FDA-approved CDK4/6 inhibitor (CDK4/6i) palbociclib, and identify additional targets engaged by narazaciclib. Activity was measured by exposing narazaciclib and other CDK4/6 inhibitors (CDK4/6i's) to panels of resistant, mutated, or modified tumor cell lines to evaluate each agent's activity and potency to inhibit growth and reduce cell line viability.

Results:

• Comprehensive analysis of cellular targets: "Thermal Shift" assays affirmed that while narazaciclib and palbociclib impact a handful of similar, expected cell pathway targets, including Rb, Akt, and mTOR, narazaciclib and its main metabolite impact more kinases than palbociclib. We believe this observation could contribute to improved efficacy for narazaciclib by overcoming cancer resistance pathways not targeted by other CDK4/6i's.
• Deeper analysis in human breast and ovarian cells/cell lines: Using bioinformatics data from human cancer databases showed that high BUB1 kinase expression is associated with low survival in patients with breast and uterine corpus endometrial carcinomas (UCEC) and was degraded by low doses of narazaciclib. Western blot analysis of data from several breast cancer cell line panels (including those with known mutations or the overexpression of the membrane receptor, FGFr, an independent prognostic factor in some solid tumor cancers and a driver of resistance to CDK4/6 inhibitors), showed that narazaciclib and its metabolite resulted in a more substantial reduction in cell viability compared to other CDK4/6i's dosed as monotherapy or in combination with autophagy inhibitors. These data support the potential use of narazaciclib in breast cancer and UCEC, either as monotherapy or in combination with other agents.
• Ability to induce senescence and T-cell recruiting chemokines: Treatment with narazaciclib/metabolite produced more profound reductions in cell viability in PYMT murine breast cancer cells, compared to palbociclib and other CDK4/6i's (combined with autophagy inhibitors). In addition, narazaciclib treatment produced significantly higher increases in T-cell recruiting chemokines, including CXCL10, than palbociclib. These results suggest that narazaciclib has the differentiated potential to promote greater levels of anti-tumor immunity, which could enhance its efficacy.
  
   

Conclusions: Expansive analysis of narazaciclib and its metabolite, compared to palbociclib and other CDK4/6i's, shows that narazaciclib has the potential to be differentiated by its:

• Multi-kinase profile, including its impact on BUB1 which is associated with poor prognosis in breast and uterine cancers;
• Potent ability to inhibit cell viability in a wide range of breast and ovarian cancer cell panels, including those with common mutations and over-expression of the FGFr, with or without autophagy inhibitors;
• Ability to produce significantly higher increases in T-cell recruiting chemokines and promote greater anti-tumor immunity.
  
   

These data support the potential use of narazaciclib in patients with breast and ovarian cancer, as well as its potential in LGEEC, based on broad, differentiated multi-kinase activity, supported by potential anti-tumor activity and anti-tumor immunity, compared to palbociclib and other CDK4/6i's. Evaluation across a range of cell lines, mutations, and prognostic factors, with or without autophagy inhibitors, underscores the strength and consistency of these data.

Posted In: ONTX