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.

 

AACR 2017: Organoids & Neuroendocrine Prostate Cancer

nepc organoidsAt the American Association for Cancer Research (AACR) 2017 Annual Meeting, researchers and physicians from Weill Cornell Medicine and NewYork-Presbyterian presented updates on the use of organoids in neuroendocrine prostate cancer.

Dr. Mark Rubin, Director of the Englander Institute for Precision Medicine, spoke about functional testing to use organoids to determine drug sensitivity or resistance. We have previously shown the power of sophisticated genomic analysis, but the information obtained by extracting DNA or RNA from a sample is fixed in time. Organoids allow for testing of many different types of tumor processes or properties, including the examination of important cellular pathways and treatment sensitivity and resistance. For example, we can test certain drugs or drug combinations to see how well they work or don’t work on a specific tumor or tumor type. For instance, in a clinical trial to examine the response of men with neuroendocrine prostate cancer (NEPC) to a drug called alisertib, we took tissue biopsies before the patients started treatment. From these tissues, we developed organoids. We then used these organoids to test response to alisertib. Treating the organoids with the drug showed the same results as in the patients (one with an exceptional response and the other with treatment resistance).

LoredanaLoredana Puca, PhD, a postdoctoral associate mentored by Drs. Beltran and Rubin, highlighted the similarities in the microscopic anatomy of the cells and tissues (also referred to as the histology) between the organoids and the original biopsy tissue at the 2017 AACR meeting. Additionally, she presented results showing how the tumor’s DNA (also referred to as the genomics), as well as way the cells encode RNA to create proteins (also referred to as transcriptomics) – both of which are integral to the tumor’s ability to grow and mutate – are similar between organoids and biopsy. This sets the stage to utilize organoids for diagnostic and treatment testing in the hopes that the results will be more analogous to human tumors than traditional cell-line work.

Learn more about this research by visiting Dr. Beltran’s lab website. For additional information about organoids and how they work check out this recent blog post.

Mini Organs: What Organoids Can Tell Us

Historically, cancer research has been conducted using cell lines that grow in a petri dish. We’ve been able to learn a lot and make much progress in the fight against cancer using this approach, but it also has some limitations, as the environment is not truly reflective of the way cancer cells grow and metastasize within the human body – a three-dimensional (3-D) environment. Additionally, cell lines can mutate over time and then sometimes no longer reflect the genetic and molecular variants of cancer cells.

Over the past 10-15 years, medical research has evolved and grown (literally and figuratively) – what used to only be possible in sci-fi movies and imaginations is now a reality as we create mini-models of bodily organs in the laboratory. These 3-D structures are also known as organoids, and an exciting area of this research is related to cancerous tumors.

Cancer biopsies remove tumor cells directly from the body. Often these biopsies are conducted when a primary tumor is found and removed, and sometimes also if the cancer has grown and spread to other locations throughout the body. This is because tumor cells evolve and change over time, especially as they try to develop workarounds in response to treatment. From the tumor cells that are removed in a biopsy, we’re analyzing the pathology and learning about the cancer on the molecular and genetic level, including any mutations we may be able to target.

Another way we’re able to use these tumor cells is to grow organoids in order to replicate the tumor outside of the body. This 3-D representation of the tumor allows us to conduct research in a way that better addresses the complex structure of the cancer. It is a form of precision medicine or personalized medicine, and allows us to test how an individual patient’s cancer cells may respond to a wide range of treatments.

This video created by the Englander Institute for Precision Medicine provides an overview of how this process works: