Nelfinavir, A Lead HIV Drug for the Treatment of Multiple Myeloma

Myeloma cells have unique protein biosynthesis gear and in this aspect differ from all other types of cancer cells. Despite new insights into the pathogenesis of multiple myeloma, the best treatment option for patients with high risk multiple myeloma is not clearly understood.

Recent studies have shown the antitumor activity of protease inhibitors which is independent from their ability to inhibit HIV enzymes. Protease inhibitors (PIs) are a class of antiviral drugs that are used to treat HIV/AIDS by preventing viral replication after selectively binding to viral enzymes- proteases.

For now, nine HIV-PI have been approved (saquinavir, nelfinavir, lopinavir, amprenavir, atazanavir, darunavir, tipranavir, indinavir), most of which are structural homologs of the lead drug ritonavir with improved pharmacokinetics.

Research

work published recently in “Blood cancer Journal” characterized the effects of all approved HIV-PI on myeloma cells. Those drugs were compared based on cytotoxicity, proteasome activity and other intracellular molecular signaling pathways.

The study was designed to select the most appropriate HIV-PI for clinical trials in myeloma, to select the most appropriate target population of myeloma patients, and to identify combination partners for this drug.

Authors reported that Nelfinavir is the HIV-PI, with highest cytotoxic activity against primary myeloma cells. Moreover, Nelfinavir had superior synergistic activity with bortezomib/carfilzomib (US approved PI for relapsed multiple myeloma) in particular against resistant myeloma cells. Nelfinavir has in advance, unique proteasome inhibiting activity in intact myeloma cells.

Previously also, a landmark paper compared the cytotoxic activity of all HIV-PI and identified nelfinavir has the potentially highest antineoplastic activity in lung cancer cell lines.

There is a strong rationale to assess nelfinavir in combination with proteasome inhibitors such as bortezomib, carfilzomib or novel proteasome inhibitors in resistant myeloma in a clinical study.

The bottom line, based on their molecular properties, but also on their availability, HIV-PI are extremely interesting drugs for a potential anti-myeloma therapy.

$1 million gift to fund Ehlers Danlos syndrome research at BCM

 

HOUSTON — (August 14, 2013) —  With a new $1 million gift, Baylor College of Medicine geneticist Dr. Brendan Lee hopes to broaden understanding of the mechanisms of Ehlers Danlos syndrome, an incurable, inherited connective tissue disorder in which the body does not make enough collagen, resulting in weakened tendons and ligaments and ultimately poor skin healing and hypermobile joints.

Given by Dr. And Mrs. David Ott, the gift will establish the Pamela and David Ott Fund for Heritable Disorders of Connective Tissue and Ehlers Danlos syndrome (EDS).

No cure

The severity of the disorder varies by individual from mild to life-threatening. There is no cure, but supportive treatment is offered.

“There have been great advances in the understanding of heritable disorders of connective tissues especially affecting bone, cartilage, and blood vessels,” said Lee, the Robert and Janice McNair Endowed Chair in Molecular and Human Genetics and a professor of genetics at BCM. “Through studying disorders that affect these organs like Osteogenesis Imperfecta, Achondroplasia and Marfan syndrome, much has been learned and new therapies developed.”

Genetic diseases of soft tissue

There is an enormous area of unmet need regarding genetic diseases of soft tissue and joints that affect tendons, ligaments and skin, said Lee, also an investigator of the Howard Hughes Medical Institute.

The new fund will form the foundation for research programs to understand the mechanism of these diseases and to treat weak tendons, ligaments and skin. This will help galvanize future efforts to translate basic findings to clinical practice in patients with joint hypermobility, delayed wound healing, scarring, and recurrent tendon or ligamentous injury.