Tag: Research

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.

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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 amr2017@med.cornell.edu or (212) 746-1362.

Clotting and Cancer: What’s the Connection?

 

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Image Credit: National Cancer Institute (NCI)

What We Already Know

In the body, there is a tight relationship between cancer development and growth, treatment, and the clotting system. Cancer cells produce substances that “thicken” the blood, so men and women with cancer have a significantly higher risk of developing blood clots. On average, people with cancer are 4-7 times more likely to have blood clots than similar people without cancer. Additionally, patients with cancer being treated for blood clots with traditional anticoagulants have a higher risk of bleeding than patients without cancer.

The importance of this connection is highlighted by a dedicated conference, the International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC). The ICTHIC meeting features educational and scientific presentations on epidemiology, biology, prevention, and treatment of clotting and bleeding related to cancer.

The 8th meeting just took place in Bergamo, Italy. World-renowned clinicians and laboratory scientists once again met and updated colleagues. Highlights included multiple presentations and discussions about risk factors for and treatment of cancer-associated venous thrombosis, blood test-based biomarkers assessing the risk of the development or recurrence of clots, lab studies investigating the mechanisms of the tight relationship between the development, progression, and treatment of cancer and thrombosis, and clinical data regarding the treatment or prevention of blood clots in patients with cancer. Special lectures included Dr. Wolfram Ruf delivering the 4th Simon Karpatkin memorial lecture on “Targeting clotting proteins in cancer therapy” where he described years of research on tissue factors involved in cancer growth and spread (metastasis). Dr. Frederick Rickles described the history of the ICTHIC from its inception in 2001 and how the field has progressed since then with an improvement in both the science in the lab and in the treatment methods and diagnostics used in the patient clinic setting.

What’s New?

Much of this year’s conference focused on venous thromboembolism (VTE), which is most commonly manifested by deep vein thrombosis (DVT = blood clots usually in legs/pelvis) and pulmonary embolism (PE = blood clots in lungs). However, it is now clear that patients with cancer also suffer from a higher rate of arterial thrombosis, meaning that they experience a higher rate of heart attacks and stroke.

In the initial Plenary session on Epidemiology, Dr. Babak Navi, Assistant Professor of Neurology at Weill Cornell Medicine (WCM), presented data on the risk of heart attacks and stroke in women with breast cancer. In collaboration with colleagues at Memorial Sloan Kettering Cancer Center, he used data from a large database of patients with Medicare. This dataset showed that women diagnosed with breast cancer have a higher risk of a heart attack or stroke in the first year after diagnosis compared to similar women without breast cancer.

What We’ve Discovered

This year at ICTHIC, we presented data that followed up on a small pilot study presented at the 7th ICTHIC Meeting in 2014 in which Drs. Choe, Tagawa, and others from WCM’s Meyer Cancer Center and the Englander Institute for Precision Medicine utilized genomic data from men with different types of prostate cancer. Patients with advanced prostate cancer had higher expression of genes involved in coagulation and thrombosis compared to patients with early stage (localized) prostate cancer. Interestingly, patients with NEPC had different gene expression compared to patients with metastatic castration-resistant prostate cancer.

Historically, multiple studies showed that patients with cancer and blood clots had more recurrent clots compared to similar patients without cancer. This led to a change in practice starting in 2003 and now many patients use injectable medications (low molecular weight heparin) as opposed to the traditional oral medications (such as warfarin/Coumadin).

Shortly after this change in best practice, we launched a collaborative study with the University of Southern California, testing one of these injectable low molecular weight heparins (tinzaparin) for the treatment of patients with cancer and blood clots. Part of the study included regular and ongoing blood draws in order to examine the biology of the blood in these patients. In the Plenary session on the treatment of cancer-related blood clots, Dr. Tagawa from WCM and Drs. Piatek, Liebman and others from USC presented the results of this study to a global audience.

The results showed that Tinzaparin performed well when examining recurrent blood clot and bleeding rates. In addition, a blood test at the initial diagnosis of the clot called D-dimer was associated with the chance of a recurrent blood clot 6 months later. The team continues to investigate a number of additional blood test biomarkers from patients with and without blood clots in this study. We hope to be able to identify patients who are most likely to develop a blood clot and for those that do, who is most likely to have recurrence of their blood clot. In the future, this may lead to individualization of the type and/or length of treatment.

What We’re Still Trying to Find Out

WCM and other investigators continue to delve into the problem of neuroendocrine prostate cancer (NEPC), an increasingly common lethal form of the disease. Clinicians dealing with this disease believe that men with this variant of prostate cancer suffer from more blood clots than those with the more common types. However, we still don’t know whether this is related to bulkier tumors, the propensity of treating physicians to use platinum-chemotherapy (which is associated with clots), or underlying disease biology.

In addition to gaining additional insight for individual patients using biomarkers, we are also continuing to develop new drugs for the treatment of clots in patients with cancer. Several new oral agents work in patients without cancer with preliminary data in cancer patients, as well. WCM physicians are joining a global study comparing one of these new oral drugs with the standard injectable medication.