Hi-Tech Blood Biomarker Signals When a Strategic Switch in Chemotherapy Will Benefit Prostate Cancer Patients

For men with metastatic prostate cancer that grows despite hormonal therapy (also referred to as castration-resistant prostate cancer), chemotherapy has been a mainstay. The class of chemotherapy that has consistently proved to improve survival for men with advanced prostate cancer is called “taxanes.”

Taxanes target microtubules, which are structures in cells that are involved in cell division, as well as the trafficking of important proteins. In prostate cancer, one of the main ways taxane chemotherapy works to kill the cancer cells involves blocking the movement of the androgen receptor (AR) along the microtubule “tracks” towards the cell nucleus, a mechanism we discovered here at Weill Cornell Medicine.

There are two taxanes FDA-approved to treat prostate cancer, docetaxel (brand name: Taxotere) and cabazitazel (brand name: Jevtana). While the drugs are similar, men whose tumors have grown despite taking one drug often respond to the other. The challenge for oncologists has been pinpointing when exactly to switch treatments.

ScottTagawa_ASCO2016_TAXYNERGYDr. Scott Tagawa presented exciting results from a phase II clinical trial at the 2016 American Society for Clinical Oncology (ASCO) annual meeting demonstrating the power of this treatment switch, and when to make the switch.

This research came to be because we thought that we might be able to increase the number of men who respond to taxane chemotherapy with an early assessment and by changing the drug for those who have a sub-optimal response. Simply put, those with no response or only an initial minor response had their drug changed at a much earlier time point then standard practice. This resulted in a higher response rate for the patients in the study.

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In the photos from a sub optimally responding patient, almost all of the androgen receptor (AR, labeled in green) is in the nucleus (indicated by the arrow which is overlayed in blue on the right), meaning that the taxane chemotherapy treatment was unable to block AR from moving to the nucleus and thus unable to kill the prostate cancer cells.

In addition, it’s very exciting that we can examine cancer cells from a simple blood test, a process also referred to as collecting circulating tumor cells or CTCs. This allows us to assess the ability of a drug to target the pathway in real time and to tell us whether there is a positive tumor response or resistance.

These circulating tumor cells provide an opportunity for real-time molecular analysis of taxane chemotherapy and at Weill Cornell Medicine we’ve pioneered a way to examine the AR pathway with a simple blood test.

To do this we use an extremely specialized technology that captures the very small fragments or rare circulating tumor cells on a “chip.” From this chip we are able to determine which cells are responding to treatment.

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In real time, we can see taxane chemotherapy kept the (green) AR out of the (blue) nucleus area in cells from a responding patient. 

In cancer care, we are always trying to maximize treatment response rates by targeting the right cells at the right time. This promising precision medicine approach offers us one more tool to better personalize treatment and improve outcomes.

 

Dr. Tagawa Presents Updated Results of ATL101 at AACR

At the annual American Association for Cancer Research in Washington, DC last week, Dr. Scott Tagawa presented updated combined analysis of 4 Phase I and Phase II studies involving 114 patients treated with ATL101. The analysis demonstrated that PSMA imaging might be used to predict the response to ATL101 radioimmunotherapy.ATL101 is a new targeted radiotherapy experimental drug for treating prostate cancer. ATL101 combines the humanized J591 monoclonal antibody targeting prostate-specific membrane antigen (PSMA) plus the Lutetium-177 radioisotope, creating the first tumor-specific delivery system able to target radiation to radio-sensitive prostate cancer cells wherever they are in the body.

From the sponsor’s press release:

14 patients were evaluable for semi-quantitative analysis of planar gamma images acquired after injection of ATL101 (35 patients from phase I at dose of 10-75 mCi/m²; 47 patients from Phase II at dose of 65-70 mCi/m² and 39 patients from phase I with a fractionated schedule at dose of 40-90 mCi/m²). 22 patients were also evaluable after injection of Indium-111 labeled J591 and treatment by Yttrium-90 labeled J591 at dose of 5-20mCi/m². Patients were sorted into 3 groups: low PSMA expression group included one third of patients, with no uptake (18%) or with weakly positive images (16%); high PSMA expression group included one half of patients, with tumor image as intense (26%) or more intense (24%) than liver. The 16 % remaining patients had intermediate uptake.

Significant correlation was found between higher PSMA expression (high vs. low) and higher response rates (RR) to treatment defined as >30% decline in PSA (RR=32% vs. 12.5%, p=0.01). RR was itself significantly correlated to longer survival. An association between PSMA expression by imaging and reduction in circulating tumor cell counts was also found (p=0.07). Further studies will examine quantitative molecular imaging with anti-PSMA PET/CT as recently published in animal models (Morris et al, 2013 ASCO Genitourinary Cancers Symposium).

Click here to read the complete press release.

USPSTF Panel Announces Final Recommendation Against PSA Screening for Prostate Cancer

The  U.S. Preventive Services Task Force (USPSTF), a government panel, has issued a recommendation that men should not get routinely screened for prostate cancer using the PSA test. The panel found there is little evidence that testing for PSA, or prostate-specific antigen, saves men’s lives, and that it causes too much unnecessary harm from the treatment of tumors that would never have killed them. The panel concluded that the benefit of screening was outweighed by the potential risks, which include pain, fever, bleeding, infection and problems urinating, resulting from biopsies as well as incontinence and impotence associated with the treatment of tumors that would not have otherwise caused harm. Click here to read more about this on the Prostate Cancer Foundation website, including a dissenting opinion and comments from the Prostate Cancer Foundation.

The American Urological Association, one of the most significant professional associations for urologists, oncologists, and radiation oncologists focusing on prostate cancer has provided helpful information, primarily aimed at primary care physicians.

The USPSTF recommendations in no way affects men who have already been diagnosed with prostate cancer and have received or are currently receiving treatment.  PSA remains one of the important tools to follow the results of treatment.  We suggest that you discuss your PSA results with your physician.
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