Kroetz leads new study of genetics of cancer drugs’ dose-limiting side effects

Taxanes are a class of drugs widely used to treat a variety of cancers, including breast, ovarian, lung, gastric, and head and neck. But dosages are often limited by toxic side effects—most commonly damage to the body’s peripheral nerves, causing numbness, pain, and/or hyper-sensitivity—that can require reduced or suspended treatment and which can linger for years in disease survivors.

In some patients this condition—sensory peripheral neuropathy—occurs at lower cumulative doses or with greater severity. While it is known that variations in genes account for some of this major difference in drug toxicity, currently there is no way to predict which patients, in the absence of other risk factors (e.g., diabetes, other neurotoxic drugs), are more susceptible.

UCSF School of Pharmacy faculty member Deanna Kroetz, PhD, will lead a new five-year $3.8 million study funded by the National Institutes of Health to identify genetic predictors (biomarkers) of patients at increased risk of such taxane-induced toxicity and how those genetic variants influence that risk. This work may also provide the basis for targeted therapies to prevent or treat the adverse side effect.

The Kroetz Lab, which studies genetic differences in drug response (pharmacogenomics), is based in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.

Risk likely due to combinations of genes

Previous research by Kroetz’s lab and others' has analyzed the genomes of patients receiving paclitaxel, a taxane-class drug, for genetic variants associated with the cumulative dose at onset and/or the severity of their peripheral neuropathy (i.e., genome-wide association studies). Those findings suggested that the toxic drug reaction is not associated with a single gene variant (allele) having a large pharmacogenetic effect. (For example, an allele of the CYP2D6 gene yields dangerous hypersensitivity to codeine.) Instead, it likely results from a combination of several gene variants, each individually contributing a small effect.

Takuma-sa

, CC0 1.0

In this visualization, a molecule of paclitaxel (yellow sticks) binds to subunits of alpha- and beta-tubulin—proteins that form microtubules. The drug inhibits microtubule assembly into mitotic spindles and thus blocks cancer cell division.

A study senior-authored by Kroetz and published in The Pharmacogenomics Journal in 2014 applied a recently developed mathematical modeling method to account for such additive genetic variation in an analysis of more than 850 patients receiving paclitaxel. The study provided more evidence for a genetic component to the drug-induced neuropathy, notably the additive effects of multiple gene variants, including subtle ones, such as differences in introns—portions of genes that do not code for protein molecules’ structure or function, but rather may affect their stability or expression.

The findings by Kroetz et al. further suggested that in patients suffering more severe paclitaxel side effects, variations in genes that regulate the outgrowth of axons were involved. Axons extend from nerve cells (neurons) to carry signals to other neurons; disruption of that growth may be one way that paclitaxel treatment results in neuropathies in susceptible patients.

Identifying key genes, testing their effects

The newly funded project will further test the contribution of common and rare genetic variants to taxane toxicity. (Taxanes block cancer’s uncontrolled division of abnormal cells by inhibiting the assembly of cellular microtubules into structures called mitotic spindles that divvy up chromosomes, thus preventing that key step in cell replication.)

The project will sequence the genomic data of more than 600 patients in a multi-institution study that compared paclitaxel to other chemotherapy regimens for treatment of advanced breast cancer, and then cross-reference that data with the extent and onset of drug-induced sensory peripheral neuropathy. Findings will be further tested via such pharmacogenomic analysis of paclitaxel toxicity in three other clinical studies of breast cancer treatment, and in a large bank of anonymous DNA samples paired with de-identified patient medical records at Vanderbilt University.

Finally, the Kroetz-led research will perform laboratory experiments to examine which variants found in those genome-wide association studies significantly affect the normal function of neurons, their axons, and Schwann cells (which support and insulate axons).