Category: Genitourinary Cancer

Marking their Territory: Using Cell Markers to Find Cancer and Stop its Spread

Cancer Cell Markers and AntibodyA key way to detect cancer cells in the body is to find “markers” on the cancer cells that don’t exist in healthy cells. For prostate cancer, we use a marker called the prostate specific membrane antigen (PSMA). PSMA is a protein on the cell surface of most prostate cancer cells, but it is not usually present elsewhere in the body. As a result, we’re able to use PSMA in order to track the presence of prostate cancer tumor growth and metastasis. At AACR 2016, the Weill Cornell Medicine (WCM) and Meyer Cancer Center investigators presented the results of two new studies that further hone in on the role PSMA plays in prostate cancer.

While we’ve known about the presence of PSMA for many years, we have recently discovered more about its biology and the tight relationship it has with the key driver of most prostate tumors, the androgen receptor (AR) pathway. As the AR pathway becomes more abnormal (is more dysregulated), the amount or expression of PSMA increases. This means that more aggressive tumors will have more PSMA on the cells.

How do we measure or quantify the amount of PSMA?

At the Weill Cornell Genitourinary (GU) Oncology Program, one way we do this is by using non-invasive methods to locate active tumors in prostate cancer patients. By tagging an antibody or small molecule with a particle that gives off energy, we can “see” the PSMA using imaging techniques. In this case, we can give people an injection to bring these tagged molecules into the body and then follow the “energy” the molecules are giving off with a scan that visualizes the tumors. In some cases, this approach helps us locate tumors that might otherwise be hidden.

However, we may also be able to assess the biology of tumors without a biopsy (non-invasively). To do this, we analyzed men who had undergone molecular PSMA imaging. Following infusion of the anti-PSMA monoclonal antibody J591 which was tagged with a particle, men underwent scanning. Based upon a system we previously published, we scored how bright their tumors were with the belief that brighter tumors would be more aggressive. In long-term follow up of the men who underwent imaging between 2000-2015, our hypothesis was confirmed. The men with the brighter tumors had higher rates of mortality, even among those who received the newer, better therapies. This type of non-invasive molecular imaging may assist physicians in determining prognosis, which may in turn guide therapy choices for especially aggressive cancers.

Antibodies as a Treatment Vehicle

In addition to tagging an antibody with an imaging agent, we can label J591 with a radioactive particle capable of killing the cancer cells, termed radioimmunotherapy. For more than a decade, we have delivered different versions of this therapy to patients at WCM. A phase II clinical trial published in 2013 was shown to be very successful at delivering a large, single-dose of radioimmunotherapy to patients, also showing that those patients receiving a larger dose had better response and survival (a “dose-response”). Building on the results of this trial, we hypothesized that by splitting the radiation dose and giving half initially and half two weeks later (this is called “dose fractionation”) that we would be able to ultimately deliver a higher dose of the treatment. At ASCO in 2010, we demonstrated this to be a promising approach to treatment and will be presenting a follow up expanded version of this study in June at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.

At AACR 2016, Dr. Ana Molina presented results of a pilot study of hyperfrationated (very split doses) 177Lu-J591, which delivers the radioactive particle lutetium-177 (177Lu) to tumors via the anti-PSMA monoclonal antibody J591. In this study, small doses of the radioimmunotherapy were delivered every two weeks until blood counts started to drop, as measured by the level of white blood cells and platelets. This treatment approach allowed all patients in this small study to receive a higher total dose than could be safely delivered with a large single dose. Two patients received five and six total doses of the treatment, reflecting a range 179 – 214% higher than the single large dose. As a result, this new approach to administering this type of immunotherapy with very split dosing may have long-term merit for men with advanced prostate cancers.

Today, men with advanced prostate cancer are able to benefit from a number of new treatment options, including the common oral hormonal drugs, abiraterone and enzalutamide. These hormonal drugs help decrease the burden of the cancer, maintain or improve the quality of life, and allow men to live longer. However, none of these drugs are curative, so we still need to make advancements in the field.

This is why we continue to use what we already know about cancer “markers,” such as PSMA, and to build on this knowledge in order to better diagnose and treat prostate cancers in a way that exploits these markers and keeps the cancer at bay. We are also constantly seeking new ways to better “see” and leverage these markers, and specifically PSMA, to prevent the growth and spread of prostate cancer.

Learn more about some of our current open clinical trials exploring this approach:

Doing Better on Behalf of Bladder Cancer Patients

Scott Tagawa_IMG_5903On Monday, April 18th, Dr. Scott Tagawa presented promising bladder cancer clinical trial results at the 2016 AACR Annual Meeting.

This phase II study of the antibody-drug conjugate (IMMU-132), demonstrated positive results in a group of adults with metastatic urothelial cancer who did not respond to standard chemotherapies or relapsed after receiving several rounds of the standard chemotherapy treatment regimens.

A form of immunotherapy, antibody drug conjugates are a targeted therapy that leverages the capability of monoclonal antibodies to attach to specific targets on cancer cells. By attaching a drug to the monoclonal antibodies, treatments are able to “hitch a ride” into the cancer cells.

“In this study, eighty-four percent of patients were alive at the nearly one-year mark, compared with an average overall survival of 4-9 months in similar patients who received chemotherapy regimens,” says Dr. Tagawa.

Some side effects were reported, including neutropenia, a low count of a type of white blood cells (neutrophils) in the blood and some diarrhea, but less than would be expected with the free form of the parent drug irinotecan. Irinotecan is a chemotherapy drug mostly used for the treatment of colon cancer. In the body, it is metabolized and breaks down into SN38, which is a more potent molecule. Because of its potency, it would be too toxic to deliver SN38 into the body in general.

IMMU-132 is a drug in which SN38 is linked to an antibody which recognizes Trop2. Trop2 is a protein in the surface of several different types of cells and is over-expressed on many common cancer types, including urothelial cancer. Since the drug shuttles SN38 preferentially into tumors, patients benefit from the potent drug without as many side effects as general chemotherapy.

This drug is also known as Sacituzumab Govitecan, and has already received FDA-breakthrough designation for the treatment of patients with triple negative breast cancer.

The Weill Cornell Medicine clinical trial continues to enroll patients with advanced urothelial cancers (tumors arising from the bladder, renal pelvis, and ureters). For more information about eligibility and enrollment, click here.

What a Simple Blood Test Can Reveal About Chemo and Prostate Cancer

From our personalities to our hair and eye colors, genetic variations make us who we are. When it comes to cancer, genetic variations can also share insights into who is most likely or least likely to respond to a particular treatment.

For people with advanced prostate cancer, taxane chemotherapy is the only chemo shown to improve survival. There are specific genetic markers evident in the blood that can tell us whether men are likely to respond to this treatment approach.

blood draw vials
Photo credit: National Cancer Institute (NCI)

Through a simple blood draw, we can isolate the presence of circulating tumor cells (cells that the tumor sheds into the bloodstream), to determine if men with prostate cancer have the most common and well-documented genetic variant, AR-v7. If patients have the AR-v7 variant, AR-targeted drugs, such as taxane chemotherapies won’t work effectively. This is because these therapies target the cells where testosterone binds (hormonal therapies). People with the AR-v7 variant are missing this binding location, so the hormonal therapies don’t work. It’s important to know this upfront, before starting treatment.

The second most common genetic variant we can test for is ARv-567-es. This variant actually has the opposite effect. Instead of indicating that taxanes won’t work, it indicates that taxane chemotherapies will work very well.

Unfortunately, cancer cells are pretty smart (and sneaky), so they adapt. As a result, all tumors ultimately develop drug resistance to taxanes. How the cancer cells adapt is not well-understood. With the support of the Movember Foundation and the Prostate Cancer Foundation, Weill Cornell Medicine is part of a multi-institutional initiative to study this further and ultimately find ways to prevent this resistance from occurring.

We’ve previously determined that the genetic alteration known as TMPRSS2-ERG leads to taxane resistance because ERG binds to tubulin, the molecular binding target for taxane chemotherapy. This creates a “road-block” that prevents the chemotherapy from working.

Independently, the presence of AR-v7 or ERG is already known to cause prostate cancer patients to stop responding to taxane chemotherapy. At AACR 2016, we presented new research on how ERG and AR-v7 may serve as co-conspirators when it comes to developing taxane resistance. We found that in 70% of ERG-positive advanced, metastatic prostate cancer patients, AR-v7 was also present. In this study, we also determined that ERG and AR-v7 bind together and form a protein complex. We are currently examining whether this complex targets specific genes in the cell that are known to facilitate the growth and progression of prostate cancer.

We can detect the presence of ERG and AR-v7 through non-invasive “liquid biopsies.” By isolating circulating tumor cells and analyzing the presence of genetic alterations with cutting-edge technologies, we are able to quickly determine whether a patient will respond well or show resistance to taxane chemotherapy. If we determine that someone will be resistant, we can then recommend a more effective treatment approach, saving patients time and preventing exposure to unnecessary toxicity.

Additionally, at AACR 2016, the labs of Drs. Elemento and Giannakakou presented new research using sophisticated computer software analysis to examine large datasets derived from circulating tumor cells from the blood of men with advanced prostate cancer. This method was effective in identifying gene expression differences, mutations and communication pathways within the cells that promote cancer progression.

Our ongoing research aims to use this method to analyze circulating tumor cells from patients before, during and after taxane chemotherapy treatment in order to detect differences that could be the cause of treatment resistance.