2018 in Review: Advancements and Accomplishments

From delivering exceptional care in the clinic, to presenting at scientific conferences and publishing research in high-impact medical journals, our Genitourinary (GU) Oncology Program had an exceptionally busy 2018. We continue to work diligently to develop new and more effective therapies to treat advanced prostate, bladder and kidney cancers, while educating the community about cutting-edge advancements in the field.

As we look back on 2018, we wish to share a brief update of our research and accomplishments. Here’s what our team has been up to over the past year.

New Faces
Most recently, we were proud to welcome Dr. Cora Sternberg, a global thought-leader in the GU oncology space, to our team. Dr. Sternberg will facilitate the continued growth and development of clinical and translational research programs in GU malignancies, as well as serve as Clinical Director of the Englander Institute for Precision Medicine (EIPM) to develop strategies to incorporate genomic sequencing and precision medicine within our Program and across Weill Cornell Medicine and NewYork-Presbyterian.


New Events
More than 200 prostate cancer patients and loved ones attended our inaugural New York City Prostate Cancer Summit, a multi-institutional collaboration between Weill Cornell Medicine, NewYork-Presbyterian Hospital, Columbia University Irving Medical Center and Memorial Sloan Kettering Cancer Center. This educational and advocacy event featured presentations and panel discussions from local medical experts and national advocacy leaders, with topics including nutrition, screening, coping and anxiety, immunotherapy and much more. Our second annual Summit is slated for September 2019 during Prostate Cancer Awareness Month. Stay tuned for details.


New Research Developments

Prostate Cancer

• Based upon our prior work with fractionated dosing of our radiolabeled antibody 177Lu-J591, we performed the world’s first phase 1 dose-escalation trial of 177Lu-PSMA-617 without finding any dose-limiting toxicity (no major side effects despite higher and higher doses), presenting the initial results at the European Society for Medical Oncology (ESMO) 2018 Congress. The phase II portion of the trial is ongoing. We are also leading the first trial combining two different targeting agents (J591 and PSMA-617) designed to deliver more radiation to tumors and less to other organs.

•  Alpha particles are several thousand-fold more potent than beta-emitters such as 177 Lu. We are completing the phase 1 dose-escalation portion of the world’s first-ever clinical trial utilizing a powerful alpha particle (225Ac) directed almost exclusively at prostate cancer cells by linking it with our J591 antibody, which avoids salivary glands.

• As prostate-specific membrane antigen (PSMA) targeting enters “prime time,” the United States Department of Defense (DOD) has recognized our significant contributions to this evolving field with a grant that will allow us to research optimal patient selection for PSMA-targeted radionuclide therapy and assess the treatment’s immune effects.

• Thanks to developing technology utilizing circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), we are able to draw information about a patient’s tumor via a simple blood test. In our findings published by the American Association for Cancer Research (AACR) Clinical Cancer Research journal, we analyzed the relationship between chemotherapy treatment and expression of androgen receptor (AR) variants in CTCs of men with metastatic prostate cancer.

• We led a phase II clinical trial through the Prostate Cancer Clinical Trials Consortium (PCCTC) and discovered that an aggressive subset of disease called neuroendocrine prostate cancer (NEPC) is driven by a gene with an associated target known as aurora kinase. Further investigation into targeting of the gene may help us to refine therapy for this difficult-to-treat patient population. Our findings were published as a cover story in Clinical Cancer Research. 

• Working with collaborators and funded by the Prostate Cancer Foundation (PCF), we have developed unique genomics sequencing methodology called PCF SELECT that allows us to identify actionable mutations in men with advanced prostate cancer.

Kidney Cancer

• The number of United States Food and Drug Administration (FDA)-approved drugs for patients with advanced kidney cancer continues to grow. Dr. Ana Molina leads our team in offering clinical trials focused on novel targeted agents, combination treatments, and risk-directed therapies for various subtypes of kidney cancer.

• Working together with the Englander Institute for Precision Medicine, we are evaluating genetic signatures from patient tumor specimens and developing organoids that can be used to test novel pathways and tailor treatment to each individual patient.

• Laboratory studies of our in vivo kidney cancer models have resulted in discoveries regarding the metabolism of the disease. Understanding the role of the mitochondria (a cell’s power generator) in kidney cancer is leading us to novel therapeutic approaches to block tumors from growing and spreading.

Bladder Cancer

• Five immune therapies are now FDA-approved for people with advanced bladder cancer. We continue research to improve upon these agents by combining them with targeted therapeutics with the potential to replace chemotherapy. Collaboration with EIPM will help us to identify tumors most likely to benefit from these treatments.

• Dr. Bishoy Faltas and his lab team are focused on understanding the role of a specific family of proteins that cause mutations (genetic errors) that may be the underlying cause of bladder cancer. This research will enable us to develop new treatments to target the newly-identified genes that drive the disease.

• Based upon Dr. Faltas’ prior high-impact Nature Genetics publication that identified the genetic mechanisms by which bladder cancers become resistant to chemotherapy and new drug targets, we are launching an innovative new clinical trial utilizing a targeted drug that inhibits bladder cancer growth, the first time this type of drug is being tested in bladder cancer.

• We are conducting clinical trials of two antibody-drug conjugates (sacituzumab govitecan and enfortumab vedotin) designed to deliver potent chemotherapy-like toxins preferentially to cancer cells. This type of therapy is anticipated to become one of the standard approaches to bladder cancer treatment.

Precision Medicine

• Using samples of patient tumors (drawn via needle biopsy), we can create small 3-D tumor representations known as organoids that mimic the way that cancer cells grow within the body and respond to treatment. Our team has worked to develop this exciting new form of precision medicine, which is especially significant for rare cancers with a lack of preclinical models available for study.

We are moving closer to our ultimate goal of curing genitourinary cancers and look forward to continued progress in the years ahead.

 

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.

Promising New Radioligand Treatment for Men with Metastatic Prostate Cancer Using Lutetium 177 (177Lu)

Slide1
Using small molecules, we are able to target not only the known tumors, but can also treat the unknown tumors.

Physicians and researchers at Weill Cornell Medicine have been utilizing prostate specific membrane antigen (PSMA)-directed radioisotope therapy for more than a decade. Over the years, we have shown that we could use this approach to target the vast majority of prostate cancer tumors (“hitting” essentially all known tumors and avoiding normal organs), demonstrated anti-tumor responses when the J591 antibody is linked to a radioactive particle with a large (single) treatment, and then further improved upon this treatment (while simultaneously reducing the side effects) by dose-fractionation (splitting the dose into two).

Following our lead and with the discovery of new small molecules which also specifically bind to PSMA, European physicians have begun using these compounds tagged with the same radioactive particle. The most common molecule has been termed PSMA-617. They have shown some very nice anti-tumor responses with limited side effects. However, because European laws differ from the U.S., many men are able to pay for treatment outside of the setting of rigorous, organized clinical research studies that clearly define appropriate dosing, efficacy and toxicity.

In January 2017, research was published in the Journal of Nuclear Medicine demonstrating that Lutetium 177 combined with PSMA-617 can reduce the amount of tumors in the body and lead to remission of the cancer as measured by PSA level. Twelve German hospitals reviewed their data and compiled a publication of patients with metastatic prostate cancer who received Lutetium-177 linked to PSMA-617 (177Lu-PSMA-617). Over 18 months, 145 men whose cancer grew despite standard treatments (including abiraterone and/or enzalutamide and chemotherapy) and whose tumors “lit up” on PSMA imaging were treated. While not a proper prospective research study, they were able to determine information about both anti-tumor activity and safety. Most patients who had PSA measured before and after treatment had some decline, with 40% having PSA cut at least in half following a single treatment. Blood counts dropped in less than half (usually to moderate degrees) and some developed dry mouth and/or taste changes. Severe toxicity was rare.

It is encouraging to see that there is a treatment that might lead to reduction in cancer without severe side effects, even in men who previously have received many other lines of treatment. However, both rigorous research as well as access for our patients are current issues. Therefore, we are excited to offer a clinical trial that builds upon our prior experience of anti-PSMA radioimmunotherapy while taking into account the available European data.

This study utilizes the most commonly used molecule, 177Lu-PSMA-617, in a prospective manner. Our prior research has shown that higher doses result in significantly better anti-tumor responses, so one purpose of this study is to perform dose-escalation to determine the safest and most-effective dose without increased side effects. In addition, our research demonstrated that dose-fractionation allowed higher doses with less toxicity, so our treatment schedule will deliver the total dose in 2 fractions.

We look forward to advancing science and also making these treatments available to men in the tri-state area and across the U.S., not just those who can afford to fly to Germany for treatment. At Weill Cornell Medicine and NewYork-Presbyterian, we have an excellent, multidisciplinary team that has led the world in PSMA-targeted radionuclide therapy. We will leverage our combined expertise and experience to translate the exciting knowledge base into true clinical gains for prostate cancer patients.

To learn more about the clinical trial or enroll, click here. Call us at 646-962-2072 to make an appointment or schedule a consultation.