Tag: ASCO

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.

 

ASCO 2016: Updates in Advanced Prostate Cancer and Precision Medicine

Advances in therapeutics have led to improvements in both survival and quality of life for patients with cancer, including men with advanced prostate cancer. Simultaneously, a number of cutting-edge scientific advances have been made in the underlying biology of advanced prostate cancer. There is great potential and power in integrating these new therapeutics and biomarkers, which is often referred to precision medicine. While great advances have already been made in this area, many remain highly sophisticated and restricted to selected centers, such as Weill Cornell Medicine and NewYork-Presbyterian Hospital, while others still need validation in a larger number of patients. Ultimately, the goal is to be able to bring these technologies and treatments to cancer patients all around the country and the world.

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Dr. Misha Beltran speaks to a full house at the ASCO 2016 Annual Meeting in Chicago.

At the 2016 ASCO meeting, Dr. Himisha Beltran was the chair of a session entitled “Precision Medicine in Advanced Prostate Cancer: Understanding Genomics, Androgen Receptor Splice Variants, and Imaging Biomarkers.” This session intended to demystify some of the language and updates surrounding precision medicine.

Dr. Beltran spoke about important recent advances in tumor and patient genomics, such as the specific genetic alterations that we now know drive different types of tumors and play a role in the development of aggressive forms of the disease. The Cancer Genome Atlas (TCGA), a government-led initiative through the National Cancer Institute (NCI) has generated multi-dimensional maps for key genomic changes in 33 different types of cancer. It also provides a collaborative platform for physicians and researchers to search, download, and analyze data. Through the TCGA there have been critical discoveries regarding untreated primary prostate tumors with molecular classification of different subtypes that go beyond Gleason scores (the common way pathologists “grade” the aggressiveness of tumors).

Additionally, the first publication of the Stand Up to Cancer Prostate Cancer Dream Team demonstrated the genomic landscape of metastatic biopsies in the castration-resistant setting, which have differences compared to primary prostate tumors and fall into groups which may be targetable by certain therapies. Dr. Mark Rubin is the Weill Cornell Primary Investigator for the Stand Up to Cancer Dream Team. In addition, as follow up to Dr. Beltran’s initial 2011 publication, she detailed the results of Weill Cornell’s collaborative efforts leading to key discoveries in neuroendocrine and castration-resistant prostate cancer using tumor tissue as well as circulating tumor cell analysis.

Collaborator Dr. Gerhardt Attard presented data on utilizing DNA obtained from blood only, an emerging method of accessing the tumor’s genomic information in a non-invasive manner, which may decrease the need for a biopsy and allow for multiple samples to be assessed over time. One clinically relevant portion of his work, being done in collaboration with Drs. Beltran and Francesca DeMichelis, is ongoing through a Prostate Cancer Foundation – Movember Challenge Award grant. Together, we are leveraging our published genomic data on neuroendocrine and treatment-resistant prostate cancer with the circulating tumor DNA from blood technology to assess patients’ cancer status before, during, and after treatment.

In addition to improvements in tumor and blood-based biomarkers, imaging biomarkers are also being investigated. Dr. Michael Morris described standardizing the use of traditional scans to assess prostate cancer progression. In addition, there are a number of molecular imaging modalities that may demonstrate increased sensitivity in the detection of tumors as well as give insight into the biology of individual tumors, highlighted by prostate specific membrane imaging including the New York-based collaboration between Memorial Sloane Kettering Cancer Center and Weill Cornell Medicine investigators.

Prostate Cancer Treatment: Getting the Best Results by Targeting the Right Cells at the Right Time

Lutetium 177 (also known as Lu-177 or 177-Lu) is a very popular radioactive particle used to treat prostate cancer in Europe, as it has previously been shown to be effective against metastatic prostate cancer. For more than 10 years, Weill Cornell Medicine has been one of very few centers in the United States that is able to offer this as a targeted prostate cancer treatment.

Lutetium 177 is a radioactive material that has a short-range, which means that it can act in a targeted fashion against cancer cells with little “collateral” damage to nearby organs and tissues. It needs some help to get to these specific cancer cells though, so we combine it with the J591 monoclonal antibody that binds to a protein expressed on nearly all prostate cancer cells, PSMA. Together, this treatment compound is called 177Lu-J591.

Here’s an overview of how we use monoclonal antibodies to target cancer cells, in this case the target is the prostate cancer tumors:

The treatment approach is called radioimmunotherapy because we’re using a tiny tag of radioactive material that can kill prostate cancer cells (in this case 177Lu) and attaching it to a very specific immune-based courier (J591) to help it get inside these cells.

We already know that 177Lu-J591 can be very effective at eradicating metastatic prostate cancer cells throughout the body. In 2013, we published results from a phase II clinical trial showing that a large, single-dose of this radioimmunotherapy could be safely delivered to patients and that those patients receiving a larger dose had better response and overall survival. This is what’s called a “dose-response.”

While higher doses of 177Lu-J591 are more effective at eradicating the prostate cancer cells, higher doses also increase the likelihood of side effects, including drops in the white blood cell and platelet counts in the blood.

Building on the results of this trial and additional scientific evidence, we hypothesized that by splitting the radiation dose and giving half at the first visit and half two weeks later (a process termed “dose fractionation”) that we would be able to deliver a higher dose of the treatment while minimizing the risk of these side effects.

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Dr. Tagawa presents the clinical trial results at ASCO 2016 in Chicago

Today at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Scott Tagawa presented final results utilizing this split-dosed approach.

The clinical trial showed that the most effective split-dose of 177Lu-J591 was 45 mCi/m2 given in two sessions, two weeks apart, a dose 28% higher than was achievable with a large single-dose. Nearly 90% of the patients in this group experienced a decline in PSA levels, resulting in an average overall survival of more than four years. In addition, the number of circulating tumor cells (also known as CTCs or prostate cancer cells floating in the blood) was decreased or controlled by treatment. In addition to this study, the lower effect of fractionated therapy on blood counts has allowed combination of this therapy with chemotherapy.

This research was supported by the Department of Defense, Prostate Cancer Foundation and the National Institutes of Health.