2019 in Review: Advancements and Accomplishments

We are proud to report another year of meaningful patient connections, exciting treatment developments and continued leadership in the field of genitourinary (GU) oncology.

Check out our team’s 2019 highlights.


NEW FACESVlachostergios Panagiotis

Panagiotis “Panos” Vlachostergios, MD, PhD, has joined our team to grow GU oncology patient care and research at NewYork-Presbyterian Brooklyn Methodist Hospital. This is a significant step in our plan to bring our world-class expertise directly to patients who live in Brooklyn, minimizing their expenses and travel time to Manhattan.


NEW EVENTS

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In addition to our digital efforts to inform the patient community of the latest news and cutting-edge advancements in the GU oncology field, we also provide opportunities to learn directly from experts via free educational events. In May, Dr. Ana Molina led our first Kidney Cancer Patient Education Symposium, which allowed kidney cancer patients to connect with one another over information sessions ranging from immunotherapy treatment to anxiety management.

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Then, during Prostate Cancer Awareness Month in September, Weill Cornell Medicine and NewYork-Presbyterian Hospital teamed up with Memorial Sloan Kettering Cancer Center and Columbia University Herbert Irving Comprehensive Cancer Center to host over 300 patients, loved ones and healthcare professionals for our 2nd Annual NYC Prostate Cancer Summit. This education and advocacy event was packed with discussions about new therapies and technologies, prostate cancer genetics, post-treatment sexual health and more.

Save the Date!
Please mark your calendar for the 3rd Annual NYC Prostate Cancer Summit on September 12, 2020, and look out for a combined Kidney and Bladder Cancer Patient Education Event in 2021.


NEW RESEARCH DEVELOPMENTS

Bladder/Urothelial Cancer

• A subset of bladder cancers are driven by the FGFR gene. We led accrual of the clinical trial that resulted in U.S. Food and Drug Administration (FDA) approval of the first targeted therapy for bladder cancer, erdafitinib, which targets the FGFR gene. This research was published in the prestigious New England Journal of Medicine.

• Immunotherapy has transformed the treatment of patients with advanced bladder cancer, but, unfortunately, only a fraction of patients respond. Dr. Bishoy Faltas led a seminal publication characterizing urothelial carcinoma that originates in the “upper tract” (center of the kidney and ureter tubes). His paper deciphers why some tumors are less likely to respond to immunotherapy and explores ways to increase response rates.

• Dr. Faltas also led work that identified the genetic mechanisms by which bladder cancers become resistant to chemotherapy and new drug targets. Based on his research, we have launched a trial of an oral targeted therapy for patients who are ineligible or choose not to receive chemotherapy prior to surgery.

• We continue to lead the development of antibody-drug conjugates, which deliver potent chemotherapy preferentially to tumor cells. In this novel therapeutic approach, a monoclonal antibody binds to specific proteins found on cancer cells, allowing the attached drug to target the cancer cells without damaging the patient’s healthy cells. One of these drugs (enfortumab vedotin) was FDA-approved in December 2019, and we are studying new combinations in earlier lines of therapy. We are also leading the pivotal clinical trial designed to get one of these antibody-drug conjugates (sacituzumab govitecan aka IMMU-132) FDA-approved and made widely available to patients. Exciting trial results were highlighted at the 2019 Genitourinary Cancers Symposium and the 2019 Congress of the European Society for Medical Oncology (ESMO).

Prostate Cancer

• Our team is at the forefront of utilizing prostate-specific membrane antigen (PSMA)-targeted therapies in the treatment of prostate cancer, currently one of the most exciting research areas in the field. We anticipate that our clinical trials will lead to FDA approval of at least one drug in the near future.

• Based upon prior work with fractionated dosing of our radiolabeled antibody 177Lu-J591, we performed the world’s first dose-escalation trial of 177Lu-PSMA-617, with results presented at the 2019 ESMO Congress. Our unique dose-dense regimen was well tolerated, with nearly 82 percent of men experiencing prostate-specific antigen (PSA) decline.

• We also completed the dose-escalation portion of the first alpha emitter (225Ac-J591) trial and will soon present the early results publicly. At the end of the year, we were notified of grant funding for an exciting future trial using this approach in combination with immunotherapy.

Kidney Cancer

• As the number of FDA-approved advanced kidney cancer drugs grows, our team remains focused on developing novel drug combinations and identifying which patients should be treated with which therapies in order to achieve the best outcomes. Our goal is to improve responses and decrease resistance to treatment by providing patients with unique combination therapies and genomic-driven targeted agents.

• Dr. Ana Molina is leading an exciting study of the antibody OX40 in combination with axitinib. Clinical and non-clinical observations suggest that combining the OX40 antibody – which stimulates the immune system and may stop cancer cells from growing – with axitinib may produce superior anti-tumor activity compared to one drug alone. This approach is being tested specifically in patients whose tumors have grown despite standard immunotherapy.

Precision Medicine

A major goal of our research is precision medicine, or the tailoring of therapy to an individual patient. Under the direction of Dr. Cora Sternberg, we continue to analyze genomic signatures, or unique tumor “fingerprints,” in patient tissue and blood samples to assess for real-time treatment targets and to discover new mechanisms of resistance to current therapies. A treatment target that we identified in an aggressive subset of disease termed neuroendocrine prostate cancer (NEPC) is making its way into clinical trials. In addition, we are spearheading work to develop organoids (mini 3-D cancer models) from patient tumor biopsies in order to test novel pathways and enhance drug development.

We look forward to persistent progress in 2020 and in the years ahead.

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Targeting Prostate-Specific Membrane Antigen (PSMA)

Our team is at the forefront of utilizing prostate-specific membrane antigen (PSMA)-targeted therapies in the treatment of prostate cancer.

PSMA is a protein on the surface of prostate cancer cells that enables a targeted approach to locate and image or treat these cells wherever they are in the body, even those that have escaped (metastasized) to other organs. We are able to target PSMA using different types of drugs, including small molecules and antibodies.

Targeting Prostate-Specific Membrane Antigen (PSMA)

Learn more about how we use antibodies and small molecules to target PSMA.

For examples of our work in action, browse open prostate cancer clinical trials at Weill Cornell Medicine and NewYork-Presbyterian.

Antibodies and Small Molecules: Two Different Tools to Target PSMA

Prostate-specific membrane antigen (PSMA) is a molecular marker present on the surface of virtually all prostate cancer cells. It can be targeted by different molecular agents that bind to PSMA. This enables a targeted approach to find and image or treat prostate cancer cells wherever they are in the body, including the cells that have escaped (metastasized) to other organs.

The most commonly used agents to target PSMA fall into two categories: small molecules (also known as peptides, ligands, or inhibitors) or antibodies (also termed monoclonal antibodies).

Small molecule- and antibody-based molecules that bind to PSMA have different physical characteristics and these have implications on the way the molecules circulate through the body.

For example, peptides and other small molecules that target PSMA are much smaller than antibodies – approximately 100-fold smaller. As a result of their small size, peptides are able to quickly travel through blood vessels and disperse throughout all body tissues – both normal and tumor – and they are also rapidly excreted by the kidney into the urine and bladder.

Conversely, the larger antibodies tend to stay within the circulating blood and flow more selectively through the larger, abnormal blood vessels within tumors than the vessels in normal tissues. Their large size also prevents them from being excreted by the kidneys. Because of these properties, peptides can penetrate tumors, as well as normal tissues, rapidly and then disappear from the body quickly, in minutes to hours; antibodies take longer to travel and enter the tumor, but this is compensated for by the longer amount of time they spend in the body (days to weeks) and their decreased likelihood to penetrate into normal tissues.

Imaging

From a diagnostic imaging perspective, small molecules are typically better, as the rapid excretion of the radiolabeled peptide quickly minimizes the radioactive background “noise” seen on a scan. Additionally, using small molecules means that patients can be injected with imaging agents and then undergo scans quickly thereafter (on the same day within 1-3 hours). Physicians can see good contrast of the cancerous cells compared to other parts of the body with this method. In comparison, patients must return approximately 3-8 days after infusion with a monoclonal antibody for scans. Some of the benefit of using small molecules is offset by the fact that they are excreted via the urine and accumulate in the urinary bladder. This may lead to an intense signal in the urinary bladder area of the scan, adjacent to the prostate gland and lymph nodes in the pelvis, thereby possibly obscuring these potential sites of tumor. On the other hand, some antibodies are taken up by the liver, obscuring visualization of that organ. Antibody fragments such as so-called “mini-bodies” (derived from the whole antibody), are half the size of a normal antibody, but still large enough so as not to be excreted in the urine, and as such, they may provide improved imaging of the prostate and the pelvic area. This is currently under investigation at Weill Cornell Medicine and NewYork-Presbyterian Hospital.

The nuances of these molecular targeting agents aside, it is clear that both peptide-, antibody or mini-body-based agents provide significantly improved targeted molecular imaging of prostate cancer compared with conventional modalities such as bone, CT, and MR scans and also have some advantages over glucose (FDG), sodium fluoride (bone), choline, or fluciclovine (FACBC) PET scans.

Treatment

From a therapeutic perspective, there are theoretical advantages to the faster tumor penetration of the smaller molecule targeting agents, but this may be offset by their quick disappearance and their ability to impact normal tissue. The longer time antibodies spend circulating in the body theoretically provides for a greater amount of the treatment agent to get internalized into the cancer cells, allowing greater uptake of the payload agent (such as a radionuclide) that is being delivered to kill the cancer cells. Additionally, some antibodies may also be engineered to generate an immune response.

Does uptake in different body areas lead to side effects?

The different characteristics of small molecules and antibodies confer advantages and disadvantages when targeting PSMA on cancer cells within the body. Because of their small size, small molecules/peptides can penetrate through the depths of the tumor very quickly, but they also readily target normal tissues that express low levels of PSMA such as the salivary glands, small intestine, and kidneys. When using as a therapeutic delivery vehicle, this might lead to dry mouth, nausea, or delayed kidney damage. Luckily, no significant kidney damage has been seen in humans to date, but the number of patients treated on prospective clinical trials remains small and follow up is short. An antibody, on the other hand, does not target salivary glands or kidneys because its larger size leads to relatively restricted access to those normal sites. However, it circulates in the body for a longer period of time including high flow through the bone marrow. Antibodies tagged with radioactive particles may therefore contribute to non-specific side effects such as temporary decreased blood counts. This is a common (expected) toxicity related to the dose and schedule of the radiolabeled antibody.

Currently, it is not known whether peptide-based or antibody-based targeted PSMA prostate cancer treatments provide better results, but both approaches offer therapeutic benefit to patients. At Weill Cornell Medicine and NewYork-Presbyterian Hospital – where we have almost two decades of experience pioneering prostate cancer imaging and treatment with PSMA-targeted agents – we are the only center in the world currently able to offer both types of imaging and treatment modalities and plan to combine both within individual patients. We hypothesize that will be able to use the favorable properties of each targeting agent at slightly lower than maximal doses to deliver a higher amount of therapeutic payload to tumor with less to normal organs, further improving the tumor kill : side effect ratio and have initiated a clinical trial testing this approach.


References

Phase I Trial of 177lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients with Androgen-Independent Prostate Cancer

Phase II Study of Lutetium-177-Labeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Metastatic Castration-Resistant Prostate Cancer