On April 28, 2021 Olatec Therapeutics LLC (Olatec) reported the first publication from its preclinical studies with dapansutrile in selected cancer models (Press release, Olatec Therapeutics, APR 28, 2021, View Source [SID1234578829]). The data in this paper, entitled "Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion", is published in the Proceedings of the National Academy of Sciences (PNAS). Under leading investigators, including Charles Dinarello MD, Olatec’s CSO, and Mayumi Fujita MD PhD, the data show that blocking NLRP3 with oral dapansutrile resulted in a significant reduction in tumor growth and progression when compared to untreated mice with induced melanoma.
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Cutaneous melanoma is an aggressive malignancy of the skin with a high mortality rate. In melanoma patients, elevated levels of myeloid-derived suppressor cells (MDSCs) are known to correlate with stage, metastasis and poor outcomes in comparison to patients with low levels of these cells. This is due to the fact that MDSCs activation suppresses the immune response to tumor cells, ultimately leading to melanoma expansion and progression. Activation and amplification of MDSCs are largely due to the production of IL‑1β by melanoma cells.
At present, one of the most common treatments for melanoma is immunotherapy, e.g., anti-PD-1 therapy, which stimulates the immune system to kill tumor cells. Despite the significant benefit to and improved prognosis of patients with advanced melanoma treated with anti-PD-1 therapy, a significant proportion of patients fail to respond due to resistance to this treatment.
"Despite breakthrough immunotherapies over the last ten years, melanoma remains a clinical challenge because tumor cells escape from destruction due to upregulated IL‑1β," said Dr. Fujita. "Our studies using a melanoma model in mice show that by reducing IL‑1β with dapansutrile, the immune system returns to its active state with restoration of its antitumor functions. As a result, melanoma tumor growth was reduced in mice. Our data further demonstrate that dapansutrile in combination with immunotherapy restores the host’s antitumor response and results in a greater reduction in the melanoma tumor than either treatment alone."
Dr. Dinarello added, "Targeting NLRP3 with dapansutrile to inhibit IL‑1β represents a new strategy for treating melanoma and other inflammatory tumors, especially to augment response rates to anti-PD-1 antibodies and to overcome resistance to other immunotherapies."
Underscoring the relevance of these ground-breaking preclinical studies, Damaris Skouras, co-Founder and CEO, said, "Based upon the positive data from our preclinical studies in melanoma, Olatec is positioned for a clinical trial to study dapansutrile in combination with a PD-1 inhibitor with the objective of inhibiting melanoma-associated IL‑1β inflammation in order to mitigate immunotherapy resistance and prevent tumor progression."
About Melanoma
In the United States, melanoma has been estimated to be the fifth most common type of new cancer diagnosis in both men and women and the most common cause of skin cancer-related death. Furthermore, among young adults, it is the second most common invasive cancer, and according to the American Academy of Dermatology Association, 1 in every 5 people in the United States suffers from skin cancer. The incidence of melanoma is increasing worldwide with reports estimating the global melanoma therapeutics market to reach over $12 billion by 2025.
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 prevent 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 is in Phase 2 clinical development and 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 antiinflammatory properties and other promising activity in a broad spectrum of over 20 preclinical animal models including arthritis, asthma, acute myocardial infarction, contact dermatitis, multiple sclerosis, melanoma and breast cancers, spinal cord injury and Alzheimer’s disease.