Veterans Affairs

Therapeutic candidates for drug resistant multiple myeloma and other p62 mediated diseases including metabolic syndrome and Alzheimer’s disease

Selective p62-ZZ inhibitors which can decrease tumor growth and bone destruction

Medical & Biotechnology

Histopathological image of multiple myoloma. Bone marrow aspirates. Image: KGH.

Scientists funded by the U.S. Department of Veterans Affairs have developed a novel treatment for multiple myeloma. This recently patented medical technology is available via license agreement to companies that would make, use, or sell it.

Multiple myeloma (MM) is an incurable hematologic malignancy, characterized by the proliferation of plasma cells and progressive bone destruction in up to 80% of patients. Despite the introduction of novel and more potent treatment regimens including thalidomide and bortezomib, MM is still the second most prevalent hematological malignancy. Projections by the American Cancer Society indicate approximately 32,270 new cases of MM will be diagnosed in 2020 and 12,830 deaths are expected. Therefore, novel therapeutics that effectively inhibit tumor growth and overcome conventional drug resistance are urgently needed.

Cell receptor p62 is a critical mediator of cell detoxification, stress response, and metabolic programs and is commonly misregulated in cancer and neurodegerative disorders. In plays a key role in the formation of signaling complexes that result in activation of signaling complexes NF-κB, p38 MAPK and PI3K, in the marrow micro-environment of patients with MM. In contrast to treating subjects with inhibitors of each of these multiple signaling pathways activated in marrow stromal cells by MM cells (e.g., NF-κB or p38 MAPK), blocking the function of p62 should inhibit the activation of the multiple pathways mediated by p62 and have a broader effect on the bone marrow micro-environment. VA researchers have developed such inhibitors of p62 selective for the ZZ domain. (p62 contains six functional domains: an N-terminal PKC-binding PB1 domain, the central ZZ and TB modules, a LC3-interacting region, a Keap1-binding region, and the C-terminal ubiquitin associated domain.)

The novel compounds modulate p62 activity in stromal cells which can decrease tumor growth and bone destruction. They may be co-adminsitered with  dexamethasone, alkylating agents (e.g., melphalan, cyclophosamide), anthracyclines (e.g., doxorubicin), thalidomide, lenalidomide, CC-4047, bortezomib, and multi-targeted kinase inhibitors to name a few.

Do you have questions or need more information on a specific technology? Let's talk.

Contact Us