Tag: Clinical Trials

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:

2017 Genitourinary Cancers Symposium Day 3

gu_symposium_2017_img_3054The third day of the 2017 Genitourinary Cancers Symposium started with a Best of Journals session on renal cell carcinoma (the most common form of kidney cancer) and the early poster sessions focused on renal cell, testicular, penile, and urethral cancers.

The first major morning session was focused on “novel targets and controversies in advanced testicular cancer.” Experts in the field first discussed actionable targets in testicular tumors, also referred to as germ cell tumors. This session also addressed a debate regarding treatment intensification in the subset of patients with “poor prognosis” – or germ cell tumors whose blood tumor markers do not decline optimally after initial chemotherapy. This subject remains controversial, but fortunately only affects a small number of patients, as in the current treatment era, after initial chemotherapy treatment, approximately 95% of all patients diagnosed with testicular cancer will be cured.

linehanThe Keynote Lecture on renal cell carcinoma was delivered by Dr. Marston Linehan from the National Cancer Institute. He discussed the current state-of-the-art treatment which is based upon decades of research largely led by him on the genetic basis of renal cell carcinoma (RCC). Several of his discoveries about the genomics and biology of RCC have led to the current wealth of drugs available to treat this disease. One such discovery was the importance of the von Hippel Lindau gene in patients with familial cancer syndromes that also affects tumor genomics in most patients with clear cell RCC. This discovery led to investigation in targeting the VEGF pathway which is the backbone of most currently approved drugs.

The session on the diagnosis and treatment of local renal cancer (confined to the kidney) started with a presentation on the role of active surveillance or watchful observation in small renal tumors, and was followed by discussions on imaging and biopsy of renal masses. A talk about the use of ablation in small renal tumors was followed by an abstract presentation on a registry of active surveillance of patients with small renal masses.  In summary, experts in the field discussed strategies and data behind the options of imaging and/or biopsy followed by either close surveillance or minimally invasive treatment strategies for patients with small renal masses.

The oral abstract scientific presentation session featured a presentation that followed up on the morning theme of small renal masses, also discussing surveillance, imaging, and circulating biomarkers. The Mayo Clinic group highlighted the success of treating carefully selected healthy patients with cryoablation in an expert center. A novel computer-assisted technique appears to be useful in assessing response to therapy compared to standard radiology assessment. A collaborative group led by Drs. Pal and Choueiri presented results of a large group of patients who had assessment of circulating tumor DNA (cfDNA) with a commercial platform prior to first-line or subsequent lines of treatment for metastatic disease.  Additionally, an Italian group presented an abstract on changes in tumor burden and prognostic classification when patients with metastatic RCC utilize an active surveillance strategy rather than take medications or undergo a local procedure. This is important to realize that for carefully selected patients, just because there are metastatic (spread) tumors on scans, immediate treatment is not always necessary. Sometimes these remain stable over long periods of time without treatment and this can be discussed with experienced clinicians.

Kidneys_GU Blog_FBThe final session of the conference reviewed the opportunities and challenges in systemic therapy for advanced kidney (renal) cancer. Imaging techniques to optimally evaluate one’s response to targeted therapies was discussed, highlighting examples of successful treatment with very little change in tumor measurements by traditional techniques. For example, it’s possible for a tumor to appear the same size after treatment by standard measurement, but it can be 95% necrotic (dead) tissue and in this scenario, the patient feels better and may live longer. This would be classified as non-response (or stable disease). Unfortunately, for patients with larger or more invasive tumors, many patients are not cured with surgery alone despite normal scans elsewhere in the body. Dr. Karam reviewed the results of recently presented trials utilizing targeted therapy following surgery. While these are not quite ready for primetime, the medical community is currently awaiting the results of other studies well as current studies utilizing immune checkpoint inhibitors in combination with surgery. Drs. Vaishampayan and Jonasch discussed the multiple different treatment options available to physicians and patients with advanced RCC. Physicians were reminded to consider referral to a highly experienced center for high-dose interleukin (IL)-2, a treatment which offers long-term disease-free survival off therapy in a selected subset of patients with advanced kidney cancer. Current studies are ongoing to assess different drug combinations, as well as novel agents. The last presentation of the conference was led by Dr. Powles who presented a late-breaking abstract on the randomized phase II study of atezolizumab with or without bevacizumab versus sunitinib in patients with advanced previously untreated metastatic RCC. While not definitive, the results were intriguing and support the continuing phase III study assessing the use of the combination of atezolizumanb and bevacizumab. There are multiple new studies looking at combinations of drugs and we encourage patients interested in this type of treatment to look for sites that are enrolling.

Overall, the conference was a great opportunity for both academic and community physicians from all different specialties (including medical oncology, urology, radiation oncology, radiology, and pathology) to mix with and learn from each other.  We look forward to participating next February in San Francisco for the 2018 Genitourinary Cancers Symposium.