Nav: Home

Analysis of metastatic prostate cancers suggests treatment options

August 04, 2016

Cancer researchers have applied a comprehensive set of analytical tools to lethal cases of metastatic prostate cancer, yielding a detailed map of the complex networks of interactions among genes and proteins that enable prostate cancer cells to proliferate and evade treatment. The team also developed a computational approach for analyzing patient-specific data to help doctors choose the most effective drugs for individual patients.

The study, published August 4 in Cell, was a collaborative effort involving research teams at UC Santa Cruz and UCLA. They began with clinical tissue samples obtained at autopsy from patients with lethal metastatic prostate cancer, then performed a range of sophisticated analyses to characterize the cancer cells from each patient in unprecedented detail. A novel computational analysis of the resulting datasets produced personalized diagrams of signaling pathways in the cancer cells of each patient, the details of which suggest potential targets for therapy.

"It's like having a blueprint for each tumor. This is our dream for personalized cancer therapy, so we're not just guessing any more about which drugs will work but can choose drug targets based on what's driving that patient's cancer," said Josh Stuart, the Baskin professor of biomolecular engineering at UC Santa Cruz, director of cancer and stem cell genomics at the UCSC Genomics Institute, and a senior corresponding author of the paper.

"Therapies for metastatic prostate cancer are urgently needed," said Dr. Owen Witte, founding director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, university professor of microbiology, immunology and molecular genetics at the UCLA David Geffen School of Medicine, and a senior author of the paper. "This type of interdisciplinary research is critical as we seek to pinpoint the cellular changes occurring in aggressive prostate cancer and cross new boundaries in understanding the disease."

Cancer genomics promises to enable personalized cancer treatment by revealing the genetic mutations driving an individual patient's tumor cells. But interpreting the genomic data remains a challenge. The effects of mutations and other genetic changes in cancer cells play out in the complex networks of molecular interactions or "signaling pathways" involved in cell growth, proliferation, and other hallmarks of cancer biology. By mapping the key pathways active in prostate cancer cells, the researchers were able to identify the "master switches" in those pathways that could be targeted with drugs to disrupt the disease.

A key step in many signaling pathways is "phosphorylation," the activation or deactivation of a protein by adding a phosphate group at certain sites on the protein. The enzymes that phosphorylate proteins are called kinases, and many new cancer drugs are kinase inhibitors. A major component of the study was a comprehensive analysis of the "phosphoproteome" of prostate cancer tumors and cells, revealing changes in the phosphorylation states of cellular proteins.

Justin Drake, a postdoctoral researcher in Witte's lab at UCLA (now an assistant professor at Rutgers Cancer Institute of New Jersey), led the phosphoproteomics work, producing a new encyclopedia of protein phosphorylation in prostate cancer cells and tissues. Evan Paull, a graduate student in Stuart's lab at UC Santa Cruz (now at Columbia University), led the computational analyses, which involved integrating the phosphoproteomic data with genomic and gene expression datasets to provide a unified view of the activated signaling pathways in late stage prostate cancer. Drake and Paull are co-first authors of the paper.

"Having the phosphoproteomics data in addition to the traditional genomics and transcriptomics enabled us to get a more comprehensive view of aberrant signaling in this disease," Paull said. "We developed a method to integrate these multiple large datasets to understand what's driving the disease in individual patients."

Prostate cancer is the third most commonly diagnosed cancer in the United States. The main treatment for advanced cases is androgen deprivation, because the male sex hormones (androgens, including testosterone) stimulate prostate cancer growth. Anti-androgen therapies target either androgen synthesis or the androgen receptor. Eventually, however, most cases of metastatic prostate cancer become resistant to these therapies.

The new study revealed some of the mechanisms behind the resistance to anti-androgen therapies. According to Stuart, in many cases a mutation results in changes to the androgen receptor protein. In other cases, alternative kinase signaling pathways allow the cancer cells to keep growing even though androgen-receptor signaling is blocked.

Individual profiles based on the analysis of each patient's tumor cells revealed clinically relevant information that could be used to prioritize the drugs most likely to be effective in these cases. The tool used to generate these individual profiles goes by the acronym pCHIPS, and the researchers created an online pCHIPS resource that allows users to make patient-specific network predictions based on their own data and visualize the results using the pCHIPS methodology.

Applying these methods to prostate cancer cell lines, the researchers found that accurate predictions of drug sensitivity could be achieved using either genomics data or phosphoproteomics data alone. That's important because the comprehensive set of analyses performed on clinical samples in this study is unlikely to be available to most patients. Clinical use of genomics, however, is growing.

Stuart explained that the integrated datasets from multiple analyses enabled the researchers to build a generic model of the signaling networks involved in metastatic prostate cancer. The pCHIPS tool uses that generic model and refines it based on patient-specific data, such as the genetic mutations in a patient's cancer cells.

"For now it's a research tool, but the hope is to have a strategy like this to use in the clinic," Stuart said. "These mutations in the genome create a lot of havoc in the cell, and trying to interpret the genomic information can be overwhelming. You need the computer to help you make sense of it and find the Achilles heel in the network that you can hit with a drug."
-end-
This research was supported by grants from the National Institutes of Health, Department of Defense, American Cancer Society, Prostate Cancer Foundation, and Stand Up to Cancer. (The Stand Up to Cancer Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant is made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.)

University of California - Santa Cruz

Related Prostate Cancer Articles:

ASCO and Cancer Care Ontario update guideline on radiation therapy for prostate cancer
The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario today issued a joint clinical practice guideline update on brachytherapy (internal radiation) for patients with prostate cancer.
Patient prostate tissue used to create unique model of prostate cancer biology
For the first time, researchers have been able to grow, in a lab, both normal and primary cancerous prostate cells from a patient, and then implant a million of the cancer cells into a mouse to track how the tumor progresses.
Moffitt Cancer Center awarded $3.2 million grant to study bone metastasis in prostate cancer
Moffitt researchers David Basanta, Ph.D., and Conor Lynch, Ph.D., have been awarded a U01 grant to investigate prostate cancer metastasis.
New findings concerning hereditary prostate cancer
For the first time ever, researchers have differentiated the risks of developing indolent or aggressive prostate cancer in men with a family history of the disease.
Prostate cancer discovery may make it easier to kill cancer cells
A newly discovered connection between two common prostate cancer treatments may soon make prostate cancer cells easier to destroy.
New test for prostate cancer significantly improves prostate cancer screening
A study from Karolinska Institutet in Sweden shows that a new test for prostate cancer is better at detecting aggressive cancer than PSA.
The dilemma of screening for prostate cancer
Primary care providers are put in a difficult position when screening their male patients for prostate cancer -- some guidelines suggest that testing the general population lacks evidence whereas others state that it is appropriate in certain patients.
Risk factors for prostate cancer
New research suggests that age, race and family history are the biggest risk factors for a man to develop prostate cancer, although high blood pressure, high cholesterol, vitamin D deficiency, inflammation of prostate, and vasectomy also add to the risk.
Prostate cancer is 5 different diseases
Cancer Research UK scientists have for the first time identified that there are five distinct types of prostate cancer and found a way to distinguish between them, according to a landmark study published today in EBioMedicine.
UH Seidman Cancer Center performs first-ever prostate cancer treatment
The radiation oncology team at UH Seidman Cancer Center in Cleveland performed the first-ever prostate cancer treatment April 3 using a newly-approved device -- SpaceOAR which enhances the efficacy of radiation treatment by protecting organs surrounding the prostate.

Related Prostate Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#530 Why Aren't We Dead Yet?
We only notice our immune systems when they aren't working properly, or when they're under attack. How does our immune system understand what bits of us are us, and what bits are invading germs and viruses? How different are human immune systems from the immune systems of other creatures? And is the immune system so often the target of sketchy medical advice? Those questions and more, this week in our conversation with author Idan Ben-Barak about his book "Why Aren't We Dead Yet?: The Survivor’s Guide to the Immune System".