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:

Aggressive Prostate Cancers: What’s New in Research and Treatment?

This year, approximately 180,000 men in the United States will be diagnosed with prostate cancer. Prostate cancer comes in many forms and we have a slew of acronyms to help us categorize not just the stage of the prostate cancer, but its various sub-types. These sub-types are based on biological markers and the genetic makeup of the tumor and tell us a lot about how the tumor may behave. We have even found that these tumor cells can change over time to avoid detection, and in the process they can become resistant to treatments.

Aggressive prostate cancer sub-types represent approximately 25% of all prostate cancer cases. A common treatment for aggressive prostate cancer that hasn’t spread (non-metastatic prostate cancer) is “castration” through surgery or other therapies to deplete the androgen and testosterone hormones that feed the tumor.

Castration-resistant prostate adenocarcinoma or CRPC is the medical term for prostate cancer that does not respond to these therapies. Adenocarcinoma is a fancy way of saying a glandular cancer, an umbrella term for cancers that originate in different glands in the body, of which the prostate is one.

Microscopic images of aggressive prostate cancers. Top: castration-resistant prostate cancer (CRPC) Bottom: Neuroendocrine prostate cancer (NEPC)

New and emerging research has shown that CRPC can evolve and morph into neuroendocrine prostate cancer (NEPC), another aggressive type of prostate cancer. The mechanism by which this happens is not yet completely known, but at Weill Cornell Medicine we’re hard at work to discover the answers.

On a molecular level, neuroendocrine prostate cancers are associated with over-expression and gene amplification of MYCN (the gene that encodes the N-Myc protein). MYCN is a gene that has been proven to drive cancer (a.k.a. an oncogene) in several rare tumor types, but the role it plays in the progression of prostate cancer has not yet been well established.

On Sunday, April 17th at the 2016 American Association for Cancer Research (AACR) Annual Meeting, Dr.
Rickman and colleagues
showed that by integrating a novel genetically-engineered mouse model and human prostate cancer transcriptome data (the product of the genes that were expressed in those patients’ tumors), N-Myc over-expression leads to the development of poorly differentiated, invasive prostate cancer that is similar to human neuroendocrine prostate cancer tumors on molecular and histological levels.

NMYC slide[1] copyThis research also demonstrated that N-Myc over-expression sensitizes cells to specific inhibitors targeting epigenetic modifiers that are linked to neuroendocrine prostate cancers. In plain language, this means that the controllers of the genes (the epigenome) in NEPC may be especially sensitive to certain drugs (such as EZH2 inhibitors that are in the clinic currently). This provides strong rationale for developing additional new therapeutic strategies in order to treat this aggressive subtype of prostate cancer more effectively and prevent it from becoming neuroendocrine prostate cancer.

For more information about our open clinical trial using an EZH2 inhibitor, please contact Amelyn Rodriguez, RN at or (212) 746-1362.

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.

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