Tag: Research

Chemo and Prostate Cancer: Not All Treatments (or Cancers) are Created Equal

By Scott Tagawa, M.D.

In casual conversations, chemotherapy is often referred to as one type of cancer treatment, but it actually refers to different classes of drugs/medications that work via a similar mechanism.

Taxanes are the only class of cheTagawa_Prostate Cancer_Chemotherapymotherapy agents that have significantly improved survival in men with advanced prostate cancer. These include docetaxel (Taxotere ®) and cabazitaxel (Jevtana ®). Though there have been exciting advances in hormonal therapies, bone-targeted therapies, and immunotherapies that have led to a multitude of FDA-approved therapies for patients, chemotherapy is a mainstay.

Chemotherapy was initially approved because men with advanced prostate cancer felt better and in less pain after receiving it. In 2004, docetaxel chemotherapy was approved because it made men feel even better than the older chemotherapy and it also controlled the prostate cancer well enough to lead to longer lifespan. However, the use of chemotherapy was initially limited due to fears of side effects and since 2011, additional medicines have been approved.

The recent success in large clinical trials using taxane chemotherapy has demonstrated unprecedented survival advantages when these drugs are used early. The CHAARTED and STAMPEDE trials showed a much larger improvement in survival compared to any treatment that has been studied in the modern era. Additional trials of men with earlier stages of prostate cancer have also pointed towards patient benefit. However, not all men respond to this treatment and despite improvements in quality of life for symptomatic men with advanced cancer, side-effects do exist. As a result, there is interest in identifying markers that can more accurately identify patients who will respond to this treatment and those for whom taxane chemotherapy is less likely to work. Many efforts are already in the works and progress has already been made.

A genetic alteration known as TMPRSS2-ERG that was co-discovered by Weill Cornell Medicine (WCM)’s Dr. Mark Rubin, Director of the Caryl and Israel Englander Institute for Precision Medicine, is unique to prostate cancer and present in tumors in about 50% of men with prostate cancer. Interestingly, we later discovered that the protein created by this gene fusion called ERG binds to tubulin, which is the molecular target of taxane chemotherapy.

Because of this protein’s interaction with tubulin, there is interference with the “drug-target engagement” of taxanes, leading to resistance. With this scientific discovery, in addition to outlining the mechanism and demonstrating drug-resistance in lab experiments, WCM investigators in collaboration with a group in Sydney tested tumors from human patients that received docetaxel chemotherapy. In this small group of men, those whose tumors expressed ERG were less likely to respond to docetaxel.

In a recent publication, Spanish investigators built on this discovery and identified TMPRSS2-ERG as a biomarker present in the bloodstream, making it a potentially easy way to use a blood test to predict resistance to taxane chemotherapy. This group of scientists from Barcelona used a blood test in men with advanced prostate cancer prior to starting docetaxel or cabazitaxel chemotherapy to determine the presence of TMPRSS2-ERG. Their work confirmed that men with tumors harbouring the gene fusion have resistance to this type of chemotherapy.

Though additional research is ongoing (and needed), there are now a number of treatment choices available. In the near future, physicians might be able to pick the drug that is most likely to work on an individualized basis, perhaps even through a simple blood test. This is another step towards our goal of precision medicine: the right treatment for the right patient at the right time.

What are Cancer Neoantigens? The Link Between Neoantigens and Immunotherapy

By Bishoy Faltas, M.D.

Our immune system has evolved over time to enable us to fight infections. Our bodies need to differentiate between our own cells (self) and cells from bacteria and viruses (non-self) in order to mount an effective attack to eliminate the invaders. In order to do that, our immune system has learned to recognize fragments of foreign proteins, which carry a specific sequence that marks them as “targets” for the immune system. We call these antigens.

Cancer cells thrive because they hide from the immune system, but their disguise is not perfect. Cells typically become cancerous because of changes in their genetic makeup. These same changes can result in proteins that the immune system is able to recognize as foreign. These are called neoantigens, and refer to new cancer antigens that cue the immune system to attack the cancer and eliminate it.

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New sequencing technologies enable us to detect new cancer antigens unique to each patient.
The immune system just needs a little help to make this happen. To tip the balance in favor of the immune system, we now use drugs called immune checkpoint inhibitors. These unleash the power of the immune system to attack the tumor. A good way to think about it is as “releasing the brakes” off the immune response. This approach to treatment is very promising for bladder cancer, especially when other treatments have failed to stop the cancer from progressing or metastasizing to other organs.

To understand which patients are most likely to respond to these immune checkpoint inhibitors, we conducted a study examining the neoantigens in bladder cancer patients at Weill Cornell Medicine. Our analyses found many differences in the neoantigens between untreated tumors and advanced tumors that had previously been treated with chemotherapy from advanced chemotherapy-resistant bladder cancers. More details on our findings can be found here:

In the future, we are hoping to use neoantigens as biomarkers that tell us which patients are most likely to respond to specific immunotherapies. A form of precision medicine, this will help us to narrowly tailor our treatment approach to each patient.

Some of our current immunotherapy treatments for people with bladder cancers include:

Partnering to Detect Prostate Cancer

By Scott Tagawa, M.D.

Prostate cancer comes in many forms. Some tumors, however anxiety producing, are slow-growing tumors and simply require monitoring. And then, there are aggressive tumors that need treatment as soon as possible. Some times these aggressive tumors even spread microscopically prior to surgery or radiation without us knowing. By finding better ways to detect the types of prostate cancers that need to be treated, and as early as possible, we increase our cure rates and the number of people we’re able to treat effectively, while simultaneously minimizing interventions for those who don’t need them.

So where do we begin when it comes to detecting these aggressive tumors? And differentiating them from their less-aggressive counterparts?

Molecular imaging holds many of these answers, particularly for prostate cancer, as it offers a non-invasive way to detect the presence of cancer and distinguish between aggressive and non-aggressive sub-types. At the Weill Cornell Genitourinary (GU) Oncology Program, we’ve had a longstanding expertise in using molecular imaging to better diagnose and treat cancer.

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(Left) A traditional bone scan only shows one small possible site of metastases in the shoulder region of the bone, compared with the molecular imaging scan of the same patient (right) which indicates many metastases throughout the body.

Through our collaboration across multidisciplinary teams and with industry partners, at our academic medical center we have developed several imaging compounds, such as 99Tc-MIP 1404. This is a radiotracer used to more clearly “see” prostate cancer cells through their expression of the prostate-specific membrane antigen (PSMA). PSMA is a key biomarker in prostate cancer that is present on nearly all tumors. By using this target as a tracer, we can sometimes detect sites of tumors that were not evident on standard types of scans. In addition, the level of PSMA evident in prostate cancer cells can indicate whether the cancer is of a higher grade, more aggressive tumor within the prostate. Our patients were among the first to have received access to this technology. We’re currently leading a clinical trial that is pivotal to the FDA ultimately approving the widespread use of 99Tc-MIP 1404 to detect prostate cancer and help us ultimately determine the best course of treatment.

In part, due to this collaborative work, we were able to recruit the inventor of some of these imaging compounds, Dr. John Babich, to Weill Cornell Medicine in 2013. Collaboration is critical to scientific progress, and we are proud to be building on these accomplishments and forming new strategic partnerships in order to bring scientific discoveries to our patients more quickly than we would be able to if everyone worked in isolation.

It was recently announced that Weill Cornell Medicine has now formed a new research collaboration with Senior Scientific, LLC to investigate using non-radioactive magnetic nanoparticles to detect and diagnose prostate cancer. The combination of molecular nuclear medicine imaging with the magnetic relaxometry (MRX) technology may lead to improvements for many of the thousands of men facing the diagnosis of prostate cancer. We look forward to working with Dr. John Babich to bring MRX technology to our patients and will keep you apprised of research progress.