On October 3, 2023 Olatec Therapeutics LLC (Olatec), a leader in the developing class of oral selective NLRP3 inhibitors, reported a publication in Cancer Research Communications showing a reduction in tumor progression with dapansutrile as a monotherapy, resulting from inhibition of NLRP3/IL-1β pathway in mouse models of pancreatic ductal adenocarcinoma (PDAC) (Press release, Olatec Therapeutics, OCT 3, 2023, View Source [SID1234635614]). Additionally, the data show that dapansutrile, when administered in combination therapy with gemcitabine significantly increased efficacy of this chemotherapy.
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PDAC has been reported to constitute ninety percent of all pancreatic cancers and it is the third leading cause of cancer deaths in the US and seventh worldwide. Long-term survival among PDAC patients remains poor due to a lack of effective screening methods, nonspecific symptoms, and limited treatment options. While there has been improvement in systemic chemotherapy, an urgent need still exists for an effective treatment.
Inflammation in the tumor microenvironment (TME) in PDAC models caused by activation of the IL-1β pathway has been shown to promote PDAC cell proliferation, metastasis and to limit response to chemotherapy. Olatec’s preclinical studies advance this understanding by demonstrating that NLRP3 participates in the IL‑1β-mediated PDAC progression. Dr. Carlo Marchetti, the investigator in these studies, shows NLRP3 to be highly expressed in the tissue of pancreatic tumors when compared to normal pancreatic tissue. Dr. Marchetti further demonstrates that PDAC-bearing wild type mice treated with dapansutrile significantly reduce tumor growth and mass, which was confirmatory in his studies using mice with the NLRP3 genetic deletion. Advancing Olatec’s understanding of dapansutrile’s immunologic effect in cancer, the studies also show that inhibition of NLRP3 with dapansutrile result in intra-tumoral increase in IL-2, a reduction in T-helper (Th)2 response, and an augmented activation of CD8 T cells which resulted in a favorable change in the T Cell phenotype of the TME.
When asked about the implications of these findings, Charles Dinarello MD, Olatec SAB Chair, said: "the preclinical data we have generated using a well-established murine model of PDAC provide the rationale to advance dapansutrile into a PDAC clinical trial."
Olatec’s Founder and CEO, Damaris Skouras, commented: "There is an urgent unmet need for an effective treatment to extend patient survival with this pernicious form of pancreatic cancer. We believe patient outcomes could potentially be improved if the data from our preclinical studies translate in clinic trials."
About Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma has been reported to constitute 90% of all pancreatic cancers and it is the third leading cause of cancer deaths in the US and seventh worldwide. The incidence rate for pancreatic cancer has increased by about 1% per year since the late 1990s in both men and women, according to American Cancer Society (Cancer Facts & Figures 2023). Lack of effective screening methods, nonspecific symptoms and limited treatment options are major limitations in the management of this disease that contribute to the extremely severe prognosis in pancreatic cancer patients. The 5-year survival reached approximately 11% for the first time in 2022. A combination of systemic therapy and surgery is needed to treat patients with PDAC in order to achieve the best chance at long-term outcomes. While there has been improvement in systemic chemotherapy, long-term survival among PDAC patients remains poor. Immunotherapy has increasingly become a treatment option of interest for many cancer types. The efficacy of immunotherapy to treat PDAC patients remains unclear, however, the PDAC tumor microenvironment may promote resistance to immunotherapy supporting the rationale for intervention with anti-inflammatory therapies.
About Dapansutrile
Dapansutrile (lab code: OLT1177) is an investigational small molecule, new chemical entity that specifically binds to and blocks NLRP3 (nucleotide-binding and oligomerization domain [NOD]‑, leucine rich repeat-, pyrin domain-containing 3), the sensor molecule integral in the formation of the NLRP3 inflammasome. Inflammasomes are multiprotein complexes involved in intracellular surveillance of danger signals that trigger an intense inflammatory response, via generation of bioactive IL-1β and IL-18 through caspase-1 activation. Dapansutrile has been shown to inhibit the formation of the NLRP3 inflammasome, which in turn inhibits the production of IL-1β and IL‑18. NLRP3 is one of the most characterized inflammasome sensors due to its involvement in a wide range of disorders, including sterile inflammation, infections, and rare genetic autoimmune syndromes. Dapansutrile has been well tolerated and shown to improve clinical outcomes in patients with acute gout flare (see The Lancet Rheumatology) and heart failure (see Journal of Cardiovascular Pharmacology). Dapansutrile has also been observed to have anti-inflammatory properties and other promising activity in a broad spectrum of over 20 preclinical animal models including arthritis, asthma, acute myocardial infarction (AMI), heart failure, contact dermatitis, multiple sclerosis, melanoma, pancreatic and breast cancers, spinal cord injury (SCI), Parkinson’s and Alzheimer’s disease. For a complete list of Olatec’s original publications on dapansutrile in various preclinical and clinical disease areas, please refer to Olatec’s publication page, here.