Thinking Beyond Survival – Cerebrovascular Complications of Cancer

Babak Navi_headshotBabak B. Navi, MD, MS
Stroke Center Director
Assistant Professor of Neurology
Weill Cornell Medicine | NewYork-Presbyterian

Over the past decade, there has been tremendous progress in cancer therapeutics. This includes targeted agents that act on specific receptors in cancer cells, immunotherapy which harnesses the body’s immune system to attack cancer cells, and personalized medicine whereby oncologists use different combinations of cancer drugs to optimize the chance of success based on the molecular profile of the tumor. These amazing scientific advances have led to prolonged survival for people with several cancer types, and it is possible that in the not-too-distant future, cancer will become more of a chronic disease with periodic flare-ups similar to what has occurred with diabetes and HIV. However, with this paradigm shift, long-term quality of life and well-being has become more important, and preventing diseases and complications that can affect these factors is paramount.

Stroke is the leading cause of disability in the United States. In addition, in many parts of the world, including Asia, it is the leading cause of death. In the United States alone, 800,000 people each year suffer stroke and this number is expected to rise as average life expectancy increases. Many factors can increase a person’s risk for stroke including age, hypertension, diabetes, high cholesterol, obesity, and smoking. Besides these traditional stroke risk factors, we now know that cancer and its treatments also increase the risk of stroke. In particular, patients with certain types of cancer, such as lung, pancreatic, and bladder cancers, as well as patients with metastatic disease, tend to have the highest risk. For instance, elderly patients with newly-diagnosed lung cancer face roughly an 8% risk of stroke in the first year after being diagnosed with cancer. In addition, cancer patients’ stroke risk varies with time and is highest in the first 3 months after diagnosis, when some cancer patients face up to a 3-fold higher risk of stroke than usual. It also turns out that certain necessary and potentially life-saving cancer treatments, including some forms of chemotherapy and radiation, can increase stroke risk.

At the moment, the exact reasons why cancer patients face a heightened risk of stroke are unclear. It is well known that circulating cancer cells can alter individuals’ clotting systems to promote clot formation but exactly how they do this is uncertain. Furthermore, doctors know that certain chemotherapy and radiotherapy treatments can damage blood vessels, but once again, the exact mechanisms underlying these processes are poorly understood.

At Weill Cornell Medicine and NewYork-Presbyterian, my team is actively working to determine what the exact risks of stroke are in people with newly diagnosed cancer, what clinical factors and biomarkers in blood can help doctors identify high-risk patients, and what the optimal strategies are to prevent and treat stroke in cancer patients. One particular study that we are currently enrolling into is entitled MOST-Cancer. This study uses cutting-edge ultrasound and blood tests to evaluate the predictors and mechanisms of stroke in people with cancer. If you or a loved one has cancer and are interested in learning more about these studies, please email our team at stroketrials@med.cornell.edu or call 212-746-6757.

May is National Stroke Awareness Month. The main intent of this campaign is to raise awareness about the symptoms and signs of stroke and to educate the public to call 911 if they suspect stroke. The most popular campaign is FAST, which stands for Face, Arm, Speech, and Time – Time to call 911.

If you or a companion develops unexplained facial asymmetry, arm weakness, or speech changes, you should call 911 immediately so that an ambulance is activated to provide rapid delivery to the closest stroke center. This is imperative as there are medicines and surgical procedures that have been proven to improve outcomes after stroke but these are only effective in the first few hours after stroke onset. Therefore, if stroke is suspected, do not hesitate, call 911, as it could be life saving!

Furthermore, I recommend that cancer patients have a frank discussion with their doctors about their individual risks for stroke and other cardiovascular diseases, as well as potential strategies to reduce their risks through medicines and lifestyle modifications.

We’ve made great strides in oncological care so that patients routinely get cured or live many years with their disease. Therefore, it is now time that we turn our attention to long-term quality of life, and in particular, to preventing stroke and the other secondary complications of cancer.

Stroke_BE FAST SIGN NEW

AACR 2017: PSMA Update

Jaspreet Batra_AACR 2017_PSMA
Jaspreet Batra presents this research at AACR 2017

At the 2017 Annual Meeting for the Annual Association for Cancer Research (AACR), we presented research highlighting how we’re targeting PSMA – a marker on the surface of most prostate cancer cells – with radioimmunotherapy to kill cancer cells.

Radioimmunotherapy involves attaching radioactive particles to targeted immunotherapies that go directly to the cancer cells. The monoclonal antibody we use is called J591 and will bind only to PSMA. In this research, we attached the radioactive isotope actinium-225 (225Ac) to J591. We have used J591 linked with lutetium 177 (177Lu) and yttrium 90 (90Y) to treat patients in many clinical trials in the past. We believe that since 225Ac is an alpha particle emitter with much greater energy released that each individual antibody will lead to more tumor cell death. In our experimental models presented at the 2017 AACR meeting, 225Ac-J591 was not significantly more toxic than control (similar to placebo) in mice without tumors. When we treated mice with prostate cancer tumors, there was significant tumor killing following a single injection of 225Ac-J591.

Given our long history of administering radiolabeled J591 to hundreds of men in different clinical trials, we have plans to launch a phase I dose-escalation clinical trial (to determine safe doses and later look at tumor response) later this year. We and others are quite enthusiastic about this approach.

Using Alpha and Beta Radioisotopes to Kill Cancer Cells

Radionuclides, also known as radioisotopes, are particles that emit energy. The different particles they emit vary and some types emit damaging radiation (also called ionizing particles). This is a good thing when we’re using radiation as a way to kill cancer cells. The two main categories of radiation particles used to kill cancer cells are alpha and beta particles.

Several radioisotopes – using both alpha and beta particles — have been approved by the Food and Drug Administration (FDA) for clinical use in cancer treatment. Historically, bone-seeking radioisotopes were used for patients with painful tumors in the bone. For example, Strontium-89 (Metastron) and samarium-153 (Quadramet) are beta-emitters that are taken up like calcium into bone and were approved to decrease pain. More recently, the alpha-emitting agent radium-223 (Xofigo) was approved for men with metastatic castration-resistant disease that has spread to the bone. However, unlike the previous beta-emitting agents, radium-223 was FDA-approved because it leads to longer overall survival rather than just symptom relief. Radium-223 is an alpha particle that mimics calcium and is delivered and taken up by the bone cells. This generally occurs near tumor cells, and while we don’t know the exact mechanism of action, we suspect that in addition to being in close proximity to some tumor cells, this creates a less hospitable environment for the tumor cells that have spread to the bone.

Additionally, we can now utilize different targeting agents to take radionuclides directly to the tumor cells. Radioimmunotherapy or radioligand therapy involves the practice of attaching a radioactive isotope to a cancer-targeting antibody or small molecule that binds only to a specific cancer-related molecule on a tumor cell. This is similar to a “lock and key” scenario, where the antibody or molecule resembles the key that will only recognize a very specific lock (the cancer-related molecule).

As it turns out, essentially all prostate cancer cells have a specific “lock” called prostate-specific membrane antigen (PSMA). This lock sits on the surface of each prostate cancer cell. We have engineered very specific monoclonal antibodies and molecules that will bind only to PSMA, leading to the opportunity for “molecularly targeted” (radio-)therapy.

In terms of attaching the radioactive isotopes, we can use both alpha and beta particles depending on the location and size of the tumor.Alpha vs beta radiationAlpha particles have the advantage of a very high amount of energy and a short path length. The amount of energy is high enough so that only a small number (1-10) of alpha particles lead to lethal damage to cells. An advantage of the short path length is that only the cells in close proximity to the alpha particle are destroyed, sparing other healthy and normal tissues. However, because of the short path length travelled, the alpha particle needs to be delivered into or right next to the tumor cell. In fact, even a piece of paper (or skin) is enough to block an alpha particle. Other alpha particles are being developed to be delivered as lethal payloads when attached to carrier molecules. One of these, actinium-225 (225Ac) is an alpha-emitting radionuclide that emits 4 alpha particles. In humans the 225Ac particle has been used as part of a compound linked to an antibody to treat leukemia and it also has been linked to a PSMA-recognizing peptide to treat men with late-stage prostate cancer with initial examples published last year.

Beta particles emit a lower energy, but can travel further distances. Because of their lower energy levels, more particles are required to cause lethal damage to cells.

This video provides a great overview of the process:

Additional research is needed to decipher the best radionuclides to use for which diseases in which clinical situations. We at Weill Cornell Medicine and NewYork-Presbyterian Hospital will have both alpha and beta radionuclides linked to PSMA compounds available in the clinic this year, initially with a clinical trial using 177Lu-PSMA-617, to be followed by 225Ac-J591, then the combination of 177Lu-J591 and 177Lu-PSMA-617.