On November 10, 2023 Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA), an oncology-focused drug development company, reported the publication in Molecular Cancer Therapeutics highlighting paxalisib preclinical data stemming from the research collaboration with the Huntsman Cancer Institute at the University of Utah in Salt Lake City, UT (Press release, Kazia Therapeutics, NOV 10, 2023, View Source [SID1234637631]).

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The paper by Dr Gennie Parkman and colleagues, working in the laboratory of Professor Sheri Holmen, has shown paxalisib to be active in vitro and in vivo against preclinical models of metastatic melanoma, the most aggressive form of skin cancer. Dr Parkman’s data highlights paxalisib as a dual inhibitor of both the PI3K and MTOR pathways and cites in the manuscript that paxalisib, "may represent a promising therapeutic strategy in this disease in both the first line and MAPK inhibitor resistant setting" for BRAF-mutant cutaneous melanoma.

"This is promising data for paxalisib, which reinforces its potential for use in an area outside of our traditional brain cancer areas of focus," commented Dr John Friend, Kazia’s CEO. "We are privileged to be working with one of the world’s leading melanoma centers on this outstanding research project and hope it may lead to a new way of treating melanoma for patients without suitable therapies."

Key Points from the Publication

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Activation of the PI3K / Akt / mTOR pathway, which is the target of paxalisib, is common in melanoma and has been identified as a key resistance mechanism to some established therapies.

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In vitro: Treatment with paxalisib was observed to lead to a significant decrease in melanoma cell growth in multiple cell lines and was also observed to inhibit downstream signaling through the PI3K/AKT cascade, leading to its negative effect on melanoma cell growth.

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In vivo:

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Mice bearing tumors who were dosed with 15 mg/kg paxalisib daily; paxalisib was observed to inhibit of tumor growth and significantly extended the overall survival of these mice (p=0.0003) compared to vehicle

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In a MTG004 patient derived xenograft mouse model that is resistant to dabrafenib and trametinib (inhibitors of mutant BRAF and MEK, respectively). At day 21, the mean tumor volume in the paxalisib treated mice was observed to be significantly lower than vehicle (P = .05) or dabrafenib/trametinib treated mice (P = .01)

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The authors concluded: "Our results support the use of paxalisib as a single agent either in the first line or MAPK inhibitor resistant setting for BRAF-mutant cutaneous melanoma. In this paper, we demonstrate the beneficial use of next generation PI3K/mTOR inhibitors, notably paxalisib, to inhibit melanoma cell growth."

The paper has been published online in Molecular Cancer Therapeutics and can be accessed at the following website: View Source

Melanoma

Approximately 1 in 50 people will be diagnosed with melanoma during their lifetime. Most cases are localized to the skin and can be cured through surgical resection. However, about 20% of cases spread (metastasis) and require more complex and ongoing treatment.

Melanoma represents approximately 1% of all skin cancers, but accounts for the majority of deaths from skin cancer. For melanoma that is confined to the skin at the time of diagnosis, the five-year survival rate is 99.5%. However, for melanoma that has spread to distant sites (metastatic melanoma), the five-year survival rate falls to 32%.

Approximately 50% of patients harbor activating mutations in the BRAF gene. Such patients are typically treated with the combination of a BRAF inhibitor and a MEK inhibitor. The introduction of targeted therapies has improved the average survival of patients with BRAF-mutant metastatic melanoma from approximately 6 months to approximately 24 months. However, we believe there remains a need for additional therapeutic options to further improve survival.

Next Steps

Kazia anticipates further data from the ongoing collaboration with the Huntsman Cancer Institute in CY2024. Depending on the results, Kazia may evaluate future opportunities to launch a clinical trial of paxalisib in melanoma.

This announcement was authorized for release by Dr. John Friend, CEO.