BETHESDA, MD USA (UroToday.com) - Dr. David Kwiatkowski highlighted recent genetic findings in muscle-invasive bladder cancer (MIBC). He began by showing recently published data from the journal Nature that describes the etiology of mutations in MIBC. Of course the cause has previously been ascribed to smoking, however, the publication showed that the mutations might actually be due to hyperactivity of the APOBEC family of enzymes. These enzymes are cytosine deaminases that mediate the conversion of TCW trinucleotides to TTW or TGW (where W is A or T).
He next reviewed the TCGA data for point mutation and copy number variation. Mutation or copy number changes in cell cycle proteins, kinases, and epigenetic modifiers seem to drive the disease, as they are recurrently mutated at high frequencies. Regarding receptor tyrosine kinases (RTK), EGFR is amplified in 10-15% (but not point mutated as in lung cancers), and translocations occur involving FGFR3-TACC3, which results in constitutive dimerization and activation of FGFR3. Seven tumors had viral DNA or RNA sequences, as well, although the impact of such sequences is unknown.
Dr. Kwiatkowski also focused on epigenetic changes that affect post-translational histone modification and DNA methylation. These modifications can repress or activate gene expression. Seventy-six percent of tumors had at least one inactivating mutation of an epigenetic modifier and 46% had at least 2 or more inactivating mutations. This suggests that MIBC is an epigenetic disease and that drugs targeting these pathways may be effective in this disease. Indeed, a trial for a histone-deacetylase inhibitor is underway to target patients with CBP/p300 alterations. Also, because almost all MIBCs have alterations in cell cycle proteins, CDK inhibitors or CHK1 inhibitors + gemcitabine trials are planned or underway.
Several PI3K inhibitors and mTOR inhibitors are developed or under development and are being explored in MIBC. Lastly, drugs targeting many RTK or intracellular kinases (such as EGFR, FGFR3, and MEK1/2) are also being developed and explored in MIBC. He also highlighted three high-profile “n of 1” publications describing tumor sequencing profiles associated with outlier responses to targeted therapy, such as everolimus. As was stated at the beginning of the talk by Dr. Colin Dinney, “it has been a banner year for bladder cancer.”
Presented by:
David J. Kwiatkowski, MD, PhD
Harvard Medical Center, Dana-Farber Cancer Institute, Boston, MA USA
Reported by:
Philip Abbosh, MD, PhD* from the 2014 Winter Meeting of the Society of Urologic Oncology (SUO) "Defining Excellence in Urologic Oncology" - December 3 - 5, 2014 - Bethesda, MD USA
*Fox Chase Cancer Center, Philadelphia, PA USA