Despite Genetic Probing, Pancreatic Cancer Survival Requires Phenomics
The Cancer Genome Atlas (TCGA) has allowed molecular biologists to probe the genomic landscape of different diseases.
Under the auspices of The Cancer Genome Atlas Research Network investigators have published their findings in gastric cancer, papillary thyroid cancer and others. Genomic aberrations are now being used to subcategorize broad diagnostic groups like lung or colon cancers into distinct subtypes, toward what is hoped will be better treatments.
For pancreatic carcinoma however, many of the newer “targeted” agents that inhibit genomic pathways (such as those identified by the TGCA) have provided limited benefit.
Pancreatic cancer associated with KRAS, P53 and other mutations has not, thus far, been highly responsive to the newer classes of drugs. As a result cytotoxic chemotherapy remains the principal treatment for the management of advanced pancreatic cancer.
What Our Research Has Found
As we have explored pancreatic cancer in human tumor microspheroid cultures, we have had the opportunity to develop cellular response (phenotypic) functional profiles that are not unlike the TGCA results for other cancers.
We have found that pancreatic cancer patients fall into distinct groups based on their responsiveness to drugs.
The first are those patients sensitive to many classes of drugs and who can be treated with simple cytotoxic combinations. The second are those patients resistant to virtually all drugs and who should consider experimental therapies immediately.
Another group reveals sensitivity to the Taxanes suggesting a specific predisposition to cell cycle injury at the point known as G2/M (where cells enter into mitosis). Yet another group of patients reveal Platinum and/or Irinotecan-based combinations to be their best options.
These phenotypic characterizations provide us with a clinically relevant grasp on our pancreatic cancer patients. This was the subject of a recent report (Nagourney et al, Proceedings ASCO 2015).
While we remain extremely interested in the study of signal transduction inhibitors for molecular targets like Hedgehog, WNT, PI3K and Notch, the low responsiveness that we observe for most of these agents in pancreas cancers continues to support the use of conventional (cycle specific) chemotherapy.
As we manage our pancreatic cancer patients based on phenotypic characterizations, we are seeing improved outcomes and diminished toxicities.