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.

 

Is Chemo The Best Bladder Cancer Treatment For All?

DR. SCOTT TAGAWA AND DR. BISHOY FALTAS

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The bladder is a muscular organ made up of several layers of cells. This image outlines the bladder, ureters and surrounding vessels.

State-of-the-art cancer care continues to evolve due to advances in all aspects of patient care – including diagnosis, and personalized treatment and management. By incorporating novel diagnostics, systemic therapies, molecular targeted therapies, immunotherapies, and other biotechnological strategies into treatment paradigms, patient outcomes continue to improve along the cancer continuum.

For patients with bladder cancer and other urothelial cancers (cancers of the bladder, renal pelvis and ureter), cisplatin-based chemotherapy remains the standard of care. This is based on decades of research through a series of randomized clinical trials showing that chemotherapy regimens containing cisplatin consistently lead to the best overall survival rates. Importantly, some patients with metastatic urothelial cancer who are treated with cisplatin-based regimens are cured.

However, cisplatin is hard on not just the cancer cells, but the body overall. As a result, not all patients are “fit” for cisplatin. There are standard criteria that are used to define patients for whom cisplatin is not a viable treatment option. These include kidney (renal) function as measured by a blood test and sometimes urine tests, performance status (a measure of how physically functional patients are), hearing loss, nerve damage (neuropathy/numbness), and heart failure. Some of the time, there may be trade-offs. For instance, some patients would trade off the risk of needing a hearing aid for a higher chance of tumor shrinkage (or even cure).

While it is well-known among physicians that not all bladder cancer patients are candidates for this treatment option, questions linger regarding what the best treatment option should be for these patients. To get to the bottom of this question, we reviewed the scientific evidence and Dr. Scott Tagawa recently presented our findings to a large group at the 34th annual Chemotherapy Foundation Symposium (CFS). This conference brought together over 2,000 cancer care clinicians across a multidisciplinary spectrum to provide updates on the most cutting-edge new agents, ongoing clinical trials and emerging developments in cancer treatment and diagnosis.

What did the science show?

According to recent data presented at the 2016 European Society of Medical Oncology (ESMO) meeting, the most common alternative treatment regimen for patients who are well enough to tolerate chemotherapy is the combination of carboplatin and gemcitabine chemotherapies. This was based on the review of data from 1426 patients with advanced urothelial carcinoma who were treated with chemotherapy.

Interestingly, there were some other global trends in the types of chemo prescribed. Centers that treated fewer patients with urothelial cancers were more likely to give alternative (non-cisplatin) chemotherapy to patients that did not meet any standard criteria for being unfit. The most common reason for being deemed unfit for cisplatin was the patient’s current level of kidney function. Unfortunately, data showed that patients who were fit for cisplatin, but received alternative chemotherapy lived much shorter than those who received cisplatin, and none of those patients in the study were alive at the 5-year mark.

One setting where cisplatin-based chemotherapy is very important is in the pre-operative setting where the goal is cure rather than just prolongation of life by months to years. Physicians should be aware of some “tricks of the trade” to optimize kidney function and other parameters to maximize the chance for cisplatin administration and cure. For patients, it’s important to consider at least getting a consultation at a center of excellence before making a treatment decision.

We also recently wrote an editorial in The Lancet outlining the value of immunotherapy for patients with advanced urothelial cancers who are unfit for cisplatin, and in particular checkpoint inhibitor immunotherapy. While not currently FDA-approved for this indication, a study using atezolizumab (Tecentriq) was published in this prestigious journal with a second supportive study utilizing pembrolizumab (Keytruda) presented at the ESMO meeting in October. Both studies used monoclonal antibodies that enable the immune system to become activated and fight cancer, and both demonstrated substantial responses in a subset of patients. Studies of the tumor and surrounding tissue testing for PDL1 expression are able to predict those with a higher likelihood of response, but even those with “negative” testing can respond. Tests of tumor genomics are also able to group tumors into those with a higher likelihood of response, but again, even those in the lower immune responding group can have a long-term response to immune treatment. Ongoing studies are needed to help predict response in a more powerful manner. One issue that we’ve recently examined is the difference in tumor genomics before and after chemotherapy highlighted by Dr. Faltas’ high-impact publication on the clonal evolution of urothelial cancer. Among other things, this highlights the importance of obtaining recent tissue from metastatic sites to gain the most accurate understanding of an individual patient’s tumor biology.

In summary, it is important for physicians to recognize when a patient may or may not safely receive certain chemotherapy regimens, such as cisplatin combinations in the case of urothelial carcinoma. In addition, research is ongoing for patients that are unfit for certain types of chemotherapy to prove whether or not immunotherapy should be used in patients who have not yet received chemotherapy. Several immunotherapy drugs are currently being tested in randomized clinical trials and these include patients that are unfit for cisplatin. Additionally, other drugs such as antibody-drug conjugates or monoclonal antibodies have shown promising activity in patients with advanced urothelial carcinoma, and these studies included patients unfit for cisplatin.

Clotting and Cancer: What’s the Connection?

 

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Image Credit: National Cancer Institute (NCI)

What We Already Know

In the body, there is a tight relationship between cancer development and growth, treatment, and the clotting system. Cancer cells produce substances that “thicken” the blood, so men and women with cancer have a significantly higher risk of developing blood clots. On average, people with cancer are 4-7 times more likely to have blood clots than similar people without cancer. Additionally, patients with cancer being treated for blood clots with traditional anticoagulants have a higher risk of bleeding than patients without cancer.

The importance of this connection is highlighted by a dedicated conference, the International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC). The ICTHIC meeting features educational and scientific presentations on epidemiology, biology, prevention, and treatment of clotting and bleeding related to cancer.

The 8th meeting just took place in Bergamo, Italy. World-renowned clinicians and laboratory scientists once again met and updated colleagues. Highlights included multiple presentations and discussions about risk factors for and treatment of cancer-associated venous thrombosis, blood test-based biomarkers assessing the risk of the development or recurrence of clots, lab studies investigating the mechanisms of the tight relationship between the development, progression, and treatment of cancer and thrombosis, and clinical data regarding the treatment or prevention of blood clots in patients with cancer. Special lectures included Dr. Wolfram Ruf delivering the 4th Simon Karpatkin memorial lecture on “Targeting clotting proteins in cancer therapy” where he described years of research on tissue factors involved in cancer growth and spread (metastasis). Dr. Frederick Rickles described the history of the ICTHIC from its inception in 2001 and how the field has progressed since then with an improvement in both the science in the lab and in the treatment methods and diagnostics used in the patient clinic setting.

What’s New?

Much of this year’s conference focused on venous thromboembolism (VTE), which is most commonly manifested by deep vein thrombosis (DVT = blood clots usually in legs/pelvis) and pulmonary embolism (PE = blood clots in lungs). However, it is now clear that patients with cancer also suffer from a higher rate of arterial thrombosis, meaning that they experience a higher rate of heart attacks and stroke.

In the initial Plenary session on Epidemiology, Dr. Babak Navi, Assistant Professor of Neurology at Weill Cornell Medicine (WCM), presented data on the risk of heart attacks and stroke in women with breast cancer. In collaboration with colleagues at Memorial Sloan Kettering Cancer Center, he used data from a large database of patients with Medicare. This dataset showed that women diagnosed with breast cancer have a higher risk of a heart attack or stroke in the first year after diagnosis compared to similar women without breast cancer.

What We’ve Discovered

This year at ICTHIC, we presented data that followed up on a small pilot study presented at the 7th ICTHIC Meeting in 2014 in which Drs. Choe, Tagawa, and others from WCM’s Meyer Cancer Center and the Englander Institute for Precision Medicine utilized genomic data from men with different types of prostate cancer. Patients with advanced prostate cancer had higher expression of genes involved in coagulation and thrombosis compared to patients with early stage (localized) prostate cancer. Interestingly, patients with NEPC had different gene expression compared to patients with metastatic castration-resistant prostate cancer.

Historically, multiple studies showed that patients with cancer and blood clots had more recurrent clots compared to similar patients without cancer. This led to a change in practice starting in 2003 and now many patients use injectable medications (low molecular weight heparin) as opposed to the traditional oral medications (such as warfarin/Coumadin).

Shortly after this change in best practice, we launched a collaborative study with the University of Southern California, testing one of these injectable low molecular weight heparins (tinzaparin) for the treatment of patients with cancer and blood clots. Part of the study included regular and ongoing blood draws in order to examine the biology of the blood in these patients. In the Plenary session on the treatment of cancer-related blood clots, Dr. Tagawa from WCM and Drs. Piatek, Liebman and others from USC presented the results of this study to a global audience.

The results showed that Tinzaparin performed well when examining recurrent blood clot and bleeding rates. In addition, a blood test at the initial diagnosis of the clot called D-dimer was associated with the chance of a recurrent blood clot 6 months later. The team continues to investigate a number of additional blood test biomarkers from patients with and without blood clots in this study. We hope to be able to identify patients who are most likely to develop a blood clot and for those that do, who is most likely to have recurrence of their blood clot. In the future, this may lead to individualization of the type and/or length of treatment.

What We’re Still Trying to Find Out

WCM and other investigators continue to delve into the problem of neuroendocrine prostate cancer (NEPC), an increasingly common lethal form of the disease. Clinicians dealing with this disease believe that men with this variant of prostate cancer suffer from more blood clots than those with the more common types. However, we still don’t know whether this is related to bulkier tumors, the propensity of treating physicians to use platinum-chemotherapy (which is associated with clots), or underlying disease biology.

In addition to gaining additional insight for individual patients using biomarkers, we are also continuing to develop new drugs for the treatment of clots in patients with cancer. Several new oral agents work in patients without cancer with preliminary data in cancer patients, as well. WCM physicians are joining a global study comparing one of these new oral drugs with the standard injectable medication.