A new clinical trial conducted by investigators at the Sidney Kimmel Cancer Center – Jefferson Health (SKCC) and the Lombardi Comprehensive Cancer Center at Georgetown University has generated promising results regarding a novel treatment for metastatic colorectal cancer.
Treatment options for metastatic colorectal cancer have improved significantly over the past 20 years, but most patients still experience disease progression for which there is no effective treatment. Recent scientific advances, including previous published work by SKCC investigators, for understanding colorectal cancer progression suggest that targeting the DNA repair machinery might present a new viable therapeutic strategy. Colorectal cancer cells are more genetically unstable than other types of cancer cells, indicating that they might have altered their DNA repair mechanisms in order to survive and spread. Thus, inhibiting DNA repair in colorectal cancer cells might render them more sensitive to currently used chemotherapeutic agents, potentially slowing cancer progression and enhancing survival benefits in these patients.
The group focused on inhibiting a key player in the cellular DNA repair machinery, termed poly(adenosine diphosphate ribose), known by its abbreviation PARP. PARP is an enzyme that resides in the nucleus of the cell, where it plays an important role in DNA damage repair. For the trial, patients with refractory metastatic colorectal cancer were treated with a combination of two drugs – temozolamide, which is a potent DNA-damaging agent already used alone to treat colorectal cancer, and the PARP inhibitor veliparib, to test whether the PAPR inhibitor could prime cancer cells to become more sensitive to temozolamide. A notable feature of the trial design is that three distinct patient subgroups were assessed. Of 75 total patients, 50 received a standard dose of both drugs, while 20 received an elevated dose of temozolamide in addition to the standard veliparib dosing. In addition, a small prospective group of five patients was included because they had DNA repair-deficient tumors, based on genetic profiling, and might therefore be expected to respond even more positively to drug-induced inhibition of DNA repair.
Overall outcomes from the trial were informative, and will help the team in designing new clinical trials that explore related therapeutic resistance mechanisms in metastatic colorectal cancer. The most promising findings were that the drug combinations were well tolerated by patients and resulted in modest improvements in progression-free survival and median overall survival. “The combination of PARP inhibitor therapy with another DNA-damaging agent (temozolamide) was tried based on some previous research at the lab bench, and the trial confirmed our thoughts that this combination therapy could be effective. We are encouraged to see that it was, for the most part, tolerable in these heavily pretreated patients,” Brody said.
Unexpectedly, the small patient subgroup with DNA repair machinery mutations did not respond better to the two-drug treatment, and in fact, might have experienced slightly worse outcomes. Although the latter result was preliminary due to the small sample size of five patients for this subgroup, Brody suggested that these findings, if replicated, “might rule out the possible use of these DNA damage biomarkers to predict which patients will respond best to this line of novel therapy in this cancer type.” Based on promising findings, the investigators are currently planning to expand the trial to encompass larger and different patient populations (i.e. other tumor types such as pancreatic cancers), to adjust the combinations and dosages of therapeutic agents in search of optimal regimens, and to test other potential predictive biomarkers to guide the stratification of patient subpopulations into specific treatments.