Multiple targeted therapies may be needed to combat metastatic prostate cancer because metastasis may be spread from multiple tumor clones according to a new study.
Researchers from The John Hopkins University published data in the journal Nature suggesting the existence of polyclonal seeding in human malignancy and the establishment of a clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer.1
“It was eye-opening,” said study investigator William Isaacs, PhD, who is a professor of urology at the Johns Hopkins Brady Urological Institute and a member of The Johns Hopkins Kimmel Cancer Center in Baltimore, MD. “It emphasizes the aspects that these cancers are evolving at an almost continual rate.”
Continue Reading
Using whole-genome sequencing, Dr. Isaacs and colleagues characterized multiple metastases arising from prostate tumors in 10 men with metastatic castration-resistant prostate cancer (mCRPC).
The team analyzed the subclonal architecture of prostate cancer cells and found that metastasis-to-metastasis spread was found to be common through de novo monoclonal seeding of daughter metastases.
The researchers also found a transfer of multiple tumor clones between metastatic sites in 5 of the 10 patients.
Dr. Isaacs noted that these findings are based on more than 20 years of investigation and extensive genome sequencing and bioinformatics analysis of tumor samples by scientists at the Wellcome Trust Sanger Institute, University of Tampere in Finland and members of the International Cancer Genome Consortium.
Dr. Isaacs and colleagues were able to examine with unprecedented clarity the genomic evolution of metastatic prostate cancer from initial tumorigenesis through the acquisition of metastatic potential to the development of castration resistance.
The researchers believe that a new view of mCRPC is now emerging that tumor cells share a common heritage but subclones develop metastatic potential.
The data suggest clonal diversification may occur in part as a necessity to bypass androgen deprivation therapy (ADT) and subsequently drive distinct subclones onto a convergent path of therapeutic resistance.
Dr. Isaacs said the idea that metastatic tumors can seed and establish other metastatic tumors in patients is different from traditional theories that the primary tumor is solely responsible for disseminating cancer cells with metastatic potential.
He said these new findings support the notion that treatments for metastatic cancers should include a combination of therapies that target a variety of genetic pathways.
“Different metastases have different genes and need different therapies,” Dr. Isaacs said in an interview with Cancer Therapy Advisor.
“We need to be as specific as we can in attacking specific mutations in the cancer. We need to focus on multiple therapies. We can’t ignore the heterogeneity and expect to be successful with single agents.”
The research team used a catalog of the genetic code of 51 tumors removed from 10 men who died from prostate cancer and were autopsied at The Johns Hopkins Hospital.
RELATED: Bipolar Androgen Therapy Showing Promise for Castration Resistant Prostate Cancer
The researchers compared these samples with normal tissue from each of patient which were taken between 1995 and 2004.
Whole-genome sequencing on the samples showed that even though a single cell begins the metastatic process, the disease becomes very heterogeneous as it spreads throughout the body over time.
In 5 out of 10 of the cases, the researchers found clusters of mutations present subclonally across multiple metastases.
