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.

 

Liquid Biopsies in Prostate Cancer: Ready for Prime Time?

Beltran and Lab
(From L to R) Dr. Himisha Beltran, Dr. Raymond Pastore and Dr. Bishoy Faltas

Recent studies in advanced prostate cancer have identified emerging treatment targets and mechanisms of treatment resistance. At the 2017 European Society of Medical Oncology (ESMO) Annual Meeting, Dr. Himisha Beltran chaired and moderated a session evaluating the use of liquid biopsies – blood tests used to glean information about tumors – as a useful clinical tool for prostate cancer management.

While there are no formal guidelines on who, when, how and what to test for in prostate cancer, Dr. Beltran’s expertise provided important guidance to the global oncology community on this topic, as the prospect that a blood test might reveal many insights about the cancer and the tumor makeup has led oncologists to feel excited. Several steps are still needed for broad clinical implementation.

As tumors grow, some of their cells may enter into the bloodstream. These cells are known as circulating tumor cells (CTCs) and travel throughout the body along with fragments of tumor cell DNA known as circulating tumor DNA (ctDNA). Compared with traditional biopsies which extract tissue directly from the tumor, liquid biopsies offer a less invasive way for doctors to detect molecular biomarkers and learn more about what’s going on with someone’s cancer. Liquid biopsies can also better capture tumor heterogeneity, as CTCs and ctDNA can provide a window into the entire tumor (and metastatic sites), compared with a traditional biopsy in which typically only one part of the tumor is sampled. Thus, with a simple blood test, doctors can potentially access a more comprehensive view of an individual’s cancer, which can then help them determine the best treatment for that person. Blood testing can also be more easily repeated throughout the course of treatment in order to monitor disease changes in response to therapy, so liquid biopsy offers ways to detect treatment resistance and resistance mutations early on and throughout the course of the disease.

Red Blood Cells

There is an emerging role for molecular testing in advanced prostate cancer since this information can better inform treatment decisions involving targeted therapies, such as PARP inhibitors, platinum-based chemotherapy, and immunotherapies. Liquid biopsies such as ctDNA may provide information about the genomic alterations present in the cancer, which can be used to help predict how people might respond to certain therapies.

Through liquid biopsies, physicians and researchers can also better detect signs of therapy resistance that may be emerging. For example, if a patient has a gene amplification or mutation detected in ctDNA that involves the androgen receptor (AR) gene, or AR splice variants expressed in CTCs, this may indicate that potent AR-targeted therapies may be less likely to work. This is because the cancer cells may develop various ways to reactivate androgen receptor signaling by acquiring extra copies of the AR gene (gene amplification), activating AR mutations, and/or AR splice variants (such as the AR-V7 variant), all of which result in downstream over-activity of the AR-pathway. Knowing this information up front may spare people from the side effects from a treatment likely to be ineffective. Current research is focused on developing more effective AR pathway inhibitors in this setting. CTCs may also identify other features of the cancer such as localization of the AR in response to taxanes as observed in the TAXYNERGY trial, tumor heterogeneity, and expression of emerging therapeutic targets.

Through a grant from the Prostate Cancer Foundation (PCF), Dr. Beltran and colleagues at WCM are working as part of an international consortium to develop, validate, and implement a ctDNA platform for prostate cancer. This targeted genomic sequencing test, called PCF SELECT, identifies tumor mutations in ctDNA from metastatic prostate cancer patients to guide treatment selection based on precision medicine. It is currently undergoing centralized development, and the long-term goal is that this ctDNA test will be widely used by the clinical prostate cancer community for precision medicine applications.

While liquid biopsies do have promise for these indications and can help guide decisions on the most appropriate treatments for prostate cancer patients, it is important that both patients and clinicians understand the advantages and limitations of available and emerging technologies. Undergoing treatment at a center of excellence that contributes to research on emerging trends allows individuals the opportunity to be among the first to access cutting-edge technologies that may benefit them.

 

New Clinical Trial Open for Men with Prostate Cancer

lab-researchProstate cancer grows and spreads via the androgen receptor (AR) pathway. In the beginning of treatment, most men with prostate cancer respond to androgen deprivation therapy (ADT) which cuts off this pathway. Unfortunately, the tumors are smart and evolve to create work-arounds. As a result, most men become resistant to this treatment. We call this later, more evolved form of prostate cancer, castration-resistant prostate cancer (CRPC), as it is molecularly different from the initial tumor.

taxane-figure-with-backgroundTaxane chemotherapies – docetaxel and cabazitazel– are the only treatments to demonstrate a survival benefit in men with CRPC. At Weill Cornell Medicine and NewYork-Presbyterian, we have shown that the mechanism of docetaxel taxane action in prostate cancer is inhibiting the androgen receptor pathway on the cellular level by preventing the cancer cells from being able to communicate with other cancer cells using microtubules. Dr. Scott Tagawa explains our prior research in the below video. This suggests that docetaxel may complement other therapies that target the AR pathway, including hormonal-based therapies such as ADT.

Recent trials of docetaxel plus ADT validated our scientific findings, demonstrating very impressively significant improvement in survival in men with metastatic prostate cancer who had not previously received hormonal therapy (also known as hormone-naïve metastatic prostate cancer). Taken together, these studies in both hormone-naïve and CRPC suggest that combining drugs that independently target AR signaling (what the scientific literature refers to as forming a “vertical pathway blockade”) will be more effective than sequentially using these treatments to combat the spread of the cancer.

Our recently-opened phase I study combines the approved 1st line taxane chemotherapy (docetaxel), approved potent inhibitor of testosterone production (the CYP17 inhibitor abiraterone) and a novel AR signaling inhibitor (apalutamide) in men with chemotherapy-naïve metastatic CRPC.

We hypothesize that combining these three agents that all target the same pathway using different mechanisms will result in a synergy that leads to improved cancer outcomes. We previously reported the safety and initial efficacy results of docetaxel plus abiraterone in a multicenter study. The combination was well tolerated and the preliminary efficacy results were promising, confirming the enthusiasm in the prostate cancer community to explore “early” chemotherapy combined with AR-targeted therapy for mCRPC.

As in all phase I clinical trials, there are two aims to this study. The first will provide safety and preliminary efficacy data on this combination treatment. Additionally, we will be performing molecular analysis of blood/tumor samples to identify biomarkers that are able to help predict which patients are most likely to respond to treatment, as well as to determine why some cancers become resistant to treatment. This would allow us to develop biomarker-driven clinical trials that have the potential to shift the treatment paradigm and improve outcomes for men with advanced PC.

To learn more about this clinical trial or to make an appointment with a physician in the Weill Cornell Genitourinary (GU) Oncology program, please call 646.962.2072.