'Exceptional Response' Points to New Bladder Cancer Mutations

Yael Waknine

March 24, 2014

A bladder cancer patient's exceptional 14-month response to everolimus-based therapy has led to the discovery of 2 new mTOR mutations, according to a study published online March 6 in Cancer Discovery.

The researchers, led by Jonathan E. Rosenberg, MD, from the Department of Medicine at the Memorial Sloan-Kettering Cancer Center in New York City, sought an explanation for the extraordinary response. They found that 2 novel constitutively activating mTOR mutations — E2419K and E2014K — were responsible for the tumor's exquisite sensitivity to therapy.

"The 2 mutations together caused a synergistic effect of mTOR signaling dependence in this patient. If these mutations are found in other tumors, they are likely to have similar effects, although if they are found individually rather than together, the effect could be less dramatic," Dr. Rosenberg told Medscape Medical News.

Cancer drugs can induce dramatic responses in some tumors that overexpress the target molecule and completely fail in others. These exceptional responses, defined as lasting 6 months or more in the context of an overall response rate below 10%, suggest novel pathologic mechanisms for new therapeutic targets.

"I suspect that these specific mutations are very rare," Dr. Rosenberg explained. "What was most important here was the demonstration that this type of approach — studying exceptional responses — can yield important scientific information that can then be investigated in the laboratory." It might also highlight "new and unexpected therapeutic opportunities for patients."

The index patient was the sole responder in a small phase 1 study of 9 patients with advanced solid tumors refractory to standard therapy.

All patients received 1 to 13 cycles (mean, 4 cycles) of the mTOR inhibitor everolimus combined with the VEGF receptor tyrosine kinase inhibitor pazopanib for minimal toxicity. The only other antitumor activity occurred in 3 patients with urothelial carcinoma, who remained stable for 3.8, 5.6, and 3.8 months, and in 1 patient who remained stable for 13.0 months.

Whole-exome sequencing of approximately 25,000 genes revealed 2 mTOR mutations never before identified in vivo. In vitro experiments have described E2419K as an activating mutation in the kinase domain of mTOR, and E2014K occurs in the FKBP-rapamycin-binding domain.

Using cell culture, Dr. Rosenberg's team confirmed that both mutations are activated in the mTOR pathway and are sensitive to rapamycin. The findings indicate a high likelihood of their simultaneous expression in the tumoral tissue, rendering it 100-fold more sensitive to everolimus than pazopanib.

Supporting Evidence for New Therapeutic Targets

After a stagnant 30-year pause in treatment advances for bladder cancer, genomic sequencing techniques are now blowing the field wide open.

In a study published in the March 20 issue of Nature, members of the Cancer Genome Atlas Project (TCGA) analyzed 131 high-grade muscle-invasive urothelial bladder cancers with a combination of exome-, transcriptome-, and/or whole-genome sequencing techniques.

Potential therapeutic targets were identified in 69% of the tumors, including 42% in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MPK pathway.

In another study, published in the February 11 issue of the Proceedings of the National Academy of Sciences of the United States of America, researchers from the Roswell Park Cancer Institute (RCPI) Center for Personalized Medicine in Buffalo, New York, used next-generation sequencing methods on 5 uncommon but deadly muscle-invasive transitional bladder cancers.

They uncovered a whole spectrum of genomic aberrations that fell into 2 separate molecular profiles: one group exhibited mutations of the tumor-suppressing p53 gene and were characterized by chromosomal shattering; and the other lacked evidence of chromothripsis but included amplified GRIN2A mutations usually associated with melanoma.

"Although no mTOR mutations were found in our cohort, we did find P13KCA mutations in a subset of patients. This suggests that mTOR inhibitors play a bigger role in the treatment of bladder cancer than initially anticipated because of the overlap of the PI3KCA pathway with the mTOR pathway in what is traditionally referred to as the PI3K/AKT/mTOR pathway," said lead author Carl D. Morrison, MD, DVM, in an interview with Medscape Medical News.

Dr. Morrison is executive director of the RPCI Center for Personalized Medicine and director of the division of molecular pathology.

"Several clinical trials are being planned for patients with mTOR/TSC1 and PI3 kinase pathway alterations, using various agents," Dr. Rosenberg confirmed, noting that TSC1, which has been reported to sensitize to everolimus, occurs in 7% to 8% of patients.

To New Therapeutic Targets...and Beyond

These findings also represent major advances in our understanding of bladder cancer, which resembles other tumors in its extreme molecular heterogeneity, said Matthew Galsky, MD, from the Icahn School of Medicine at Mount Sinai Tisch Cancer Institute in New York City.

"For instance, the importance of alterations in the p53/Rb pathway, RTK/PI3K pathway, and histone modification pathways are clearly demonstrated," he told Medscape Medical News.

"In addition, newly discovered potential therapeutic targets include HER2 and RXRA. Fascinatingly, the TCGA investigators demonstrated viral DNAs and transcripts in a small subset of tumors, suggesting a possible viral etiology of some bladder cancers," Dr. Galsky explained.

The TCGA study and the study by Dr. Morrison and colleagues demonstrate potential new therapeutic targets and shed light on the mechanistic basis for the molecular aberrations found in subsets of bladder cancers, transforming our understanding of "why good genes go bad," Dr. Galsky concluded.

The research by Dr. Rosenberg's team was funded by the Next Generation Fund at the Broad Institute of MIT and Harvard, the National Human Genome Research Institute, GlaxoSmithKline, and Novartis. The TCGA study was supported by the US National Institutes of Health. The Roswell Park study was supported by the National Cancer Institute. Dr. Rosenberg reports receiving commercial research grants from Novartis (the maker of everolimus, marketed as Afinitor) and GlaxoSmithKline. Dr. Morrison and Dr. Galsky have disclosed no relevant financial relationships.

Cancer Discovery. Published online March 6, 2014. Abstract

Nature. 2014;507:315-322. Abstract

Proc Natl Acad Sci U S A. 2014;111:E672- E681. Abstract

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