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UCLA Phosphoproteomic Study Finds Similarity Across Intrapatient Metastases in Prostate Cancer

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A phosphoproteomic study by researchers at the University of California, Los Angeles has found that prostate cancer metastases in different organs in the same patient share similar tyrosine kinase activation profiles.

The finding raises the possibility that personalized treatment based on analysis of a biopsy from a single metastatic lesion could prove effective across multiple sites, said Justin Drake, a postdoctoral fellow in the lab of UCLA research Owen Witte, which led the study.

"Hopefully down the line we'll be able to say that if you can take an easily accessible biopsy from a [metastatic] patient, that should be representative of the other lesions in that patient," he told ProteoMonitor.

"There's still some more investigation needed before we can conclusively make that statement," Drake said. "But we think we have some pretty strong evidence to suggest that, at least in highly treated patients, these tumors are more homogeneous in nature."

Detailed in a paper published this week in Proceedings of the National Academy of Sciences, the study used mass spec-based proteomics to profile global tyrosine phosphorylation in 16 metastatic castration-resistant prostate cancer samples from 13 different patients, including three patients featuring multiple metastases.

The researchers also analyzed one benign prostatic hyperplasia, six treatment-naïve matched benign and cancerous prostates, and metastatic or subcutaneous xenograft tumors derived from the androgen-in-sensitive 22Rv1 and androgen-sensitive LNCaP cell lines. In total, they identified 297 unique tyrosine phosphopeptides corresponding to 185 unique proteins.

Among the activated kinases identified by their analysis were several druggable kinases and pathways, including MAPK1/3 and STAT3. They also identified proteins such as ALK, EGFR, and SRC as potentially activated upstream targets. These identifications, the authors wrote, were notable given ongoing late-stage clinical trials for kinase inhibitors targeting SRC, EGFR, and ALK, as well as MEK1/2 and JAK2, which are targets upstream of MAPK1/3 and STAT3, respectively.

To investigate potential metastatic CRPC combination therapies based on their analysis of the 16 samples, the researchers pooled the kinases identified via mass spec with those identified by subsequent western blot work and kinase-substrate prediction data to identify predicted kinase activity across the samples.

Based on these predictions, they identified 11 different tyrosine kinase inhibitor combinations as potential treatments, four of which they identified as potential treatments for multiple metastases. The SRC inhibitor dasatinib – marketed by Bristol-Myers Squibb as Sprycel – was identified as a potential therapy in 14 of the 16 cases, while the MEK inhibitor trametinib – marketed by GlaxoSmithKline as Mekinist – was identified as a possible therapy in 13 cases.

Previous genomic investigations have found that CRPC metastases from different regions in the same patient exhibit similarities in copy number, mutational status, erythroblast transformation specific rearrangements, and methylation patterns, but, Drake said, the PNAS study was, to his knowledge, the first to look at this question via mass spec-based phosphoproteomics.

Indeed, he noted, such phosphoproteomic analyses of clinical cancer specimens are fairly rare as a general matter due to the challenge of obtaining enough patient material for mass spec work.

In the case of the UCLA effort, the researchers obtained samples from the University of Michigan's Rapid Autopsy Program, in which patients with the disease permit pathologists to access their tumors for research purposes upon their death. This, Drake said, allowed him and his colleagues to obtain significantly more material for their analysis than is typically possible.

Sample collection is a primary concern in phosphoproteomics work, as research, including data presented last week at the Clinical Proteomic Tumor Analysis Consortium annual symposium, has suggested that delays in freezing samples can alter phosphoproteomic profiles.

The Michigan samples are no exception, Drake said, noting that while the samples are typically extracted within several hours of the patient's death, potential phosphorylation changes during that time period "is definitely a concern."

He said, however, that the researchers "picked up pretty robust signals from activated kinases in these tissues, and they seem to be fairly robust across different metastatic lesions in the same patient."

Ultimately, Drake said, the researchers hope to scale down the mass spec sample requirements to where they can "actually look at biopsy materials in live patients."

The similarities across intrapatient metastases were observed in heavily treated patients, Drake said, noting that in pre-treated patients they would likely be more heterogeneous.

"There are some definitive mechanisms for [tumor] rewiring [in response to therapy], and a lot of it depends on what therapy you give the patient upfront," he said. "So what we think we are seeing here are resistance mechanisms to anti-androgens and docetaxel and paxitacel. What we think is that tyrosine kinase activity ramps up as a resistance mechanism to some of these therapies."

The authors noted that there was little evidence of mutations underlying the altered kinase activity, but, rather, that these changes appeared to result from changes in pathway activation. Drake said that given the relatively low mutation rates in prostate cancer, he and his colleagues went into the project under the assumption this would likely be the case.

While this might suggest that, at least in this case, phosphoproteomics would prove more informative clinically than genomic analysis, Drake noted that the former still faces challenges in convincing clinicians of its usefulness.

"Phosphoproteomics is another tool in the toolbox, and it should be used along with genetic analysis," he said. "I don't think one should necessarily be used more than the other."

"I think phosphoproteomics has a little more work to do to convince clinicians that what we find is actually clinically targetable and has therapeutic benefit, because there is plenty of evidence in the genetic arena where you've found mutations that have clinical efficacy," he added.

Over the next several years, Drake said, he and his colleagues hope to begin applying their analyses to actual patients.

"This may be a year from now or two years, but we want to take this information and test it in patient samples clinically [to see] whether combination therapies based on the information we've gathered would actually be beneficial for patients with metastatic CRPC," he said.

The researchers have begun collaborating with clinicians at UCLA and have applied for a large grant from the US Department of Defense with which they hope to launch the effort, Drake added.

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