Unlocking new potentials from established drugs is an active area of research in the life sciences industry. At General Oncology, we are developing an innovative approach to addressing the problem of BRCA-related cancer: combining a known, FDA-approved chemotherapy drug called melphalan (which is currently used only for blood cancers) with three drugs that have the potential to work together to eliminate drug resistance to melphalan. The other drugs are BCNU, vitamin B12b, and vitamin C.
The drug combination is designed for patients with Stage IV disease in the setting of an inherited BRCA1, BRCA2, or PALB2 mutation. We are currently studying this combination in the SHARON trial—a phase 1 clinical trial that is enrolling at major hospitals.
We selected melphalan because:
It has a log-linear dose-response curve in vitro. This means that doubling the exposure to the drug doubles the number of cancer cells killed, subject to certain limits. From a practical standpoint, the log-linearity of the dose-response curve implies that melphalan has the potential to give major log reductions in cancer cell survival in BRCA-related cancers. For more information about log reductions, see our article Requirements for Curing Cancer.
The primary toxicity of melphalan is to bone marrow. Bone marrow toxicity is completely reversible by an infusion of a patient’s own bone marrow stem cells. The stem cells can be collected from a patient’s blood prior to chemotherapy during a standard procedure called apheresis.
Unlike platinum drugs, melphalan generally does not cause neurotoxicity.
We selected BCNU because:
It is a DNA-damaging drug similar to melphalan. However, unlike melphalan, it diffuses into cells without the need of a transporter (melphalan requires the presence of LAT1 transporters for the drug to enter cancer cells). This is important because cancer cells that develop melphalan resistance due to the loss of LAT1 transporters can still be susceptible to BCNU.
As with melphalan, the primary toxicity of BCNU is to bone marrow. As described above, bone marrow toxicity is completely reversible.
BCNU is an irreversible inhibitor of the enzyme glutathione reductase. See below for the importance of this property.
We selected vitamin B12b because:
It catalyzes (speeds up) the conversion of vitamin C into dehydroascorbic acid (DHA) and generates hydrogen peroxide (H2O2) in the process.
Vitamin B12b does not generally cause lasting side effects.
We selected vitamin C because:
It is converted into DHA by vitamin B12b, with hydrogen peroxide being generated as a side product. DHA and hydrogen peroxide can alter the intracellular redox potential.
Unlike other drugs that can alter the intracellular redox potential, vitamin C (when given alone) is essentially nontoxic at the doses used in our drug combination.
In brief, the combination of vitamin B12b and vitamin C generates DHA and H2O2, both of which are expected to accumulate preferentially in tumor cells. In the presence of BCNU (which is an irreversible inhibitor of glutathione reductase), this is expected to increase the intracellular reduction potential. The increase in the intracellular reduction potential is expected to hypersensitize drug-resistant cancer cells to melphalan.