Era of Precision Oncology for Prostate Cancer ‘Is Upon Us’

July 10, 2016

Bryant Furlow

 

“Liquid biopsies are the way to go,” said Srinivas Pentyala, PhD, director of translational research at the Stony Brook School of Medicine in New York. Blood tests are easier to perform, and are less invasive and more convenient for patients, he said.

Others agree.

“I think CTCs and cell-free DNA will be very helpful in the future to identify men with prostate cancer who are more or less likely to benefit from a range of therapies, including docetaxel, PARP inhibitors, immunotherapies, and [androgen receptor]-directed therapies,” said Andrew J. Armstrong, MD, FACP, associate director for clinical research in genitourinary oncology at the Duke Cancer Institute in Durham, North Carolina.

There is growing demand for such tools in the clinic. Only skin cancer is more frequently diagnosed among men in the United States. More than 2.8 million US men are living with prostate cancer, and an estimated 180,890 men will be newly diagnosed in 2016, according to the National Cancer Institute (NCI).2 Currently, it is unclear which men with castration-resistant prostate cancer (CRPC) will benefit from taxane therapy and which will do better with the androgen-receptor signaling (ARS) inhibitors abiraterone and enzalutamide.3

But CRPC resistance involves AR signaling reactivation through 1 of several molecular pathways, making gene mutations in these pathways attractive targets for developing predictive biomarkers.

A recent cross-sectional study of men treated for metastatic CRPC (mCRPC) at the Memorial Sloan Kettering Cancer Center in New York, New York, strengthened the case that androgen-receptor splice variant 7 (AR-V7) plays a role in tumors’ ARS inhibitor drug resistance and is a promising biomarker for informing treatment selection decisions. The findings, published inJAMA Oncology, show that CTC expression of AR-V7 protein predicts ARS inhibitor therapy failure. Furthermore, CTC AR-V7 is associated with longer survival times among patients who were treated with taxane-based chemotherapy (overall survival [OS]: 8.9 months versus 4.6 months; P = .035).

The study utilized immunofluorescence protein assay, whereas previous work with CTC AR-V7 has used immunohistochemical (IHC) testing. While the findings are exciting, they must now be validated in prospective trials.

“There is mounting evidence on the role of AR-Vs as drivers of castration-resistance,” said William Douglas Figg, Sr, PharmD, head of the Molecular Pharmacology Section and deputy branch chief in the Genitourinary Malignancies Branch at the NCI’s Center for Cancer Research in Bethesda, Maryland, in an e-mail to Cancer Therapy Advisor. “Preclinical studies in 22RV1 cells that express both the full-length androgen receptor (AR-FL) and variant (AR-V7) suggest that inhibiting both AR-FLs and variant is necessary to inhibit tumor growth.”

He noted that cell-line studies show that AR-V7 confers resistance to both enzalutamide and abiraterone treatment, and niclosamide—a potent inhibitor of AR-V7—can re-sensitize resistant cells to both drugs.

In a commentary essay about the study, Dr Figg noted that AR-V7 itself is a promising target for drug development, and that this could change the treatment-selection implications of the AR-V7 biomarker.4

“The investigators suggest that AR-V7 status can be used to help guide optimal treatment choices by eliminating abiraterone and enzalutamide as potential therapies in AR-V7 positive status patients,” wrote Dr Figg. “Another viewpoint is that if AR-V7-targeting therapies become available then AR-V7 as a biomarker should not exclude abiraterone and enzalutamide treatment in AR-V7 positive patients; rather it should include these treatments along with an AR-V7-targeting therapy. AR-V7 detection could then help prevent treatment failure seen with abiraterone and enzalutamide.”

A phase 1 clinical trial is underway to demonstrate the efficacy of the combination of niclosamide with enzalutamide, and whether niclosamide reduces the amount of AR-V7, thereby promoting the anti-tumor effects of enzalutamide.

“It remains to be determined the effect of the combination treatment on AR-V7 expression, and monitoring for this potential biomarker is warranted as we move forward to develop novel AR-V7 inhibitors,” Dr Figg said.

Dr Armstrong is leading a multicenter prospective clinical validation study for several AR-V7 biomarker platforms among patients with mCRPC—one of several such validation studies now underway to assess which circulating biomarkers can best help to personalize clinical decision making in prostate cancer management.

“It is not a simple question,” cautioned Dr Armstrong. “Each assay has different sensitivity and clinical data and some men who are AR-V7 positive may still respond to these agents, and many men without AR-V7 detection can still be resistant to these agents.”

Dr Armstrong’s team is also examining CTC biomarkers “beyond AR” to identify new candidate tests and drug targets, he told Cancer Therapy Advisor.

Among promising prostate cancer biomarkers in development are DNA damage-repair gene mutations such as BRCA1, BRCA2, and ATM obtained from traditional tumor biopsy samples, Dr Antonarakis said.

These “may predict sensitivity to PARP inhibitors such as olaparib,” he explained.

Somatic or germline DNA damage-repair gene mutations occur in up to 20% of patients with prostate cancer, Dr Antonarakis and coauthors noted in a recent review of emerging prostate cancer biomarkers.5

PI3K/PTEN/Akt pathway-activation biomarkers and WNT signaling pathway gene aberrations are also undergoing study as molecular biomarkers that could inform prostate cancer treatment decision-making.

The search is also under way for prostate cancer RNA biomarkers, Dr Pentyala noted.5 “A recent discovery of a long noncoding RNA SChLAP1 in the prostate has provided a novel biomarker that not only adds to the ability to identify prostate cancer, but also to conventional risk stratification,” he and coauthors noted in a recent review.

The promise of DNA and RNA biomarkers is not limited to treatment selection. These tools might also prove to be a practical diagnostic tool for detecting prostate cancer at earlier tumor stages, when treatment is more effective.

“SChLAP1 has been clinically validated for the prognosis of aggressive prostate cancer and integration of genomic tests may advance the diagnosis of prostate cancer through early identification of high-risk patients,” Dr Pentyala and coauthors noted in their recent review.

When CTCs and ctDNAs are detectable, blood tests should become a “preferred choice” for early-stage diagnosis of prostate cancer, Dr Pentyala said. “We are also working on urine-based tests to see whether we can detect tumor cells sloughing off into urine from the prostate.”

“CTCs and ctDNAs reflect tumor uniqueness [and] the variation between individuals and help in targeting the specific type of tumor with therapeutics,” Dr Pentyala said.  “My only concern is, at what stage do CTCs and ctDNAs start appearing in blood. Some tumors do not shed cells as they are localized and enclosed, particularly in the prostate.”

At least until liquid biopsies’ accuracy exceeds that of tumor biopsies, however, tumor biopsy will continue to be the gold standard in characterizing prostate cancers. “If liquid biopsies are validated with 100% specificity and 100% sensitivity, they will definitely replace cumbersome tumor biopsies,” said Dr Pentyala.

 

References

  1. Beltran H, Antonarakis ES, Morris MJ, Attard G. Emerging molecular biomarkers in advanced prostate cancer: translation to the clinic. Am Soc Clin Oncol Educ Book. 2016;35:131-141.
  2. SEER Stat Fact Sheets: Prostate Cancer. US National Cancer Institute (NCI). http://seer.cancer.gov/statfacts/html/prost.html. Accessed June 22, 2016.
  3. Scher HI, Lu D, Schreiber NA, et al. Association of AR-V7 in circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol.4 Jun 2016. doi:10.1001/jamaoncol.2016.1828 [Epub ahead of print]
  4. Leibrand CR, Price DK, Figg WD. Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: biomarker for treatment selection exclusion or inclusion?Cancer Biol Ther. 2016;17(5):467-469.
  5. Pentyala S, Whyard T, Pentyala S, et al. Prostate cancer markers: an update. Biomed Rep.2016;4(3):263–268.