Phase I Study Successfully Targets Metastatic Kidney Cancer

MedicalResearch.com Interview with:

Kevin D. Courtney, M.D., Ph.D.  Assistant Professor UT Southwestern Medical Cente

Dr. Courtney

Kevin D. Courtney, M.D., Ph.D. 
Assistant Professor
UT Southwestern Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Metastatic ccRCC does not respond to traditional chemotherapy.

Current standard treatments for metastatic ccRCC include drugs called vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) that block the growth of new blood vessels that feed the cancer, as well as drugs that inhibit an enzyme called mTOR that is involved in ccRCC growth and immune therapies that rev up the body’s immune response to try to fight the cancer. Each of these treatments can have significant side effects for patients that can make them difficult to tolerate.

Metastatic ccRCC is largely incurable, and we need novel and better-tolerated treatments. A central driver of ccRCC is a protein called hypoxia inducible factor 2alpha (HIF-2alpha). This protein has been very difficult to try to target with a drug. This study is the first to test a drug that targets HIF-2alpha in patients with metastatic ccRCC. The study results showed that the HIF-2alpha inhibitor, PT2385 (Peloton Therapeutics) was active in fighting metastatic ccRCC and was well-tolerated.

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Zoledronic Acid Cost-Effective In Preventing Skeletal Events in Patients With Bone Metatstases

MedicalResearch.com Interview with:

Dr-Charles L Shapiro.jpg

Dr. Shapiro

Charles L.Shapiro MD
Professor of Medicine
Director of Translational Breast Cancer Research
Director of Cancer Survivorship
Division of Hematology/Oncology
Tisch Cancer Institute
New York, NY

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The new 2017 ASCO guidelines for the use bone-modifying in individuals with bone metastases recently endorsed every 3-month zoledronic, because of high level evidence from three randomized trials, including our trial (published in Jama in Jan 2017, first author Himelstein et al) that giving zoledronic acid every 3-months was non-inferior to the standard of monthly zoledronic. The guidelines also concluded that there was not one preferred bone modifying agent of the other, despite the fact the comparing monthly zoledronic to monthly denosumab in women with bone metastases, denosumab delayed the time to first skeletal-related event (pathological fractures, necessity for radiation or surgery, and spinal cord compression) and subsequent events by 23% (or in absolute terms about 3 months) . Zoledronic acid became generic in 2013, whereas monthly denosumab is still patented until 2022-25.

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Doubt Cast on Traditional Pattern of Cancer Metastases

MedicalResearch.com Interview with:
Benjamin Weixler, MD
Department of Surgery
University Hospital Basel, Basel, Switzerland and
Leiden University Medical Center, Leiden, the Netherlands 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: For most patients with lymph node negative colon cancer (stage I and II) surgery is regarded to be the curative treatment. Despite the curative attempt up to thirty percent of these patients will develop disease recurrence, most likely due to missed micro-metastatic disease at initial tumor staging. Pathological standard processing with hematoxylin and eosin (H&E) entails a considerable risk of missing micro-metastatic deposits in the lymph nodes. Mounting evidence indicates that micro-metastatic tumor deposits in the lymph nodes as well as in the bone marrow might be associated with an increased risk of disease recurrence and death in node negative patients. With our study we wanted to examine the correlation between the occurrence of micro-metastatic deposits in the lymph nodes and the bone marrow as well as their prognostic significance.

As a main finding, the study provides compelling evidence that tumor cell dissemination to the lymph nodes and to the bone marrow are independent events in patients with colon cancer. Most importantly did the study demonstrate that micro-metastatic deposits in the lymph nodes as well as in the bone marrow are independent negative prognostic factors regarding  disease-free and overall survival. The combined occurrence is associated with significantly worse prognosis compared to either one of them.

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Bisphosphonates Can Be Reduced In Second Year of Breast Cancer Metastases

MedicalResearch.com Interview with:

Gabriel N. Hortobagyi, MD, FACP, FASCO Professor, Department of Breast Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX 77230-1439

Dr. Gabriel Hortobagyi

Gabriel N. Hortobagyi, MD, FACP, FASCO
Professor, Department of Breast Medical Oncology
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX 77230-1439 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Bisphosphonates have been commercially available for several decades as supportive care for patients with bone metastases. They reduce the frequency and severity of bone-related complications. While the optimal dose and short-term scheduling of zoledronic acid (and previously, pamidronate) have been determined, there has been no research to determine how long these drugs need to be maintained nor the optimal dose and schedule beyond the first year of therapy. These questions are particularly important for this family of drugs, since they are incorporated into bone and not excreted from the body for many years.

We set out to determine whether a reduction in the frequency of administration of zoledronic acid (every 12 weeks) was able to maintain the therapeutic efficacy of this intervention when compared to the “standard” schedule of administration (every 4 weeks). It was a prospective, randomized, non-inferiority trial that recruited patients with metastatic breast cancer with bone metastases and who had previously received 9 or more doses of zoledronic acid or pamidronate. The primary endpoint was the proportion of patients with one or more skeletal-related events. Four hundred and sixteen patients were randomized in a 1:1 ratio. The two groups were comparable at baseline. After the first year of follow-up, there was no statistically significant difference in SRE rate between the two arms, confirming the non-inferiority fo the every-12-week schedule of zoledronic acid.

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Bisphosphonates For Bone Metastases May Be Given Less Frequently

MedicalResearch.com Interview with:

Charles L. Shapiro, MD Professor of Medicine Co-Director of Dubin Breast Center Director of Translational Breast Cancer Research Director of Cancer Survivorship, Tisch Cancer Institute Mount Sinai Health System Division of Hematology / Medical Oncology: Tisch Cancer Institute New York, NY 10029

Dr. Charles Shapiro

Charles L. Shapiro, MD
Professor of Medicine
Co-Director of Dubin Breast Center
Director of Translational Breast Cancer Research
Director of Cancer Survivorship, Tisch Cancer Institute
Mount Sinai Health System
Division of Hematology / Medical Oncology: Tisch Cancer Institute
New York, NY 10029

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Metastases to bone are frequent in many cancers and cause pain, pathological fractures, necessitate surgical and/or radiation treatments, cause spinal chord compression that can lead to paralysis, and significantly increase health care costs.

Zoledronic acid, a bisphosphonate that inhibits bone resorption, is used in standard practice because it reduces the risks skeletal-related events including cancer-related pathological fractures, the need for surgery and/or radiation to bone metastases, and spinal chord compression in patients with breast cancer, prostate cancer and multiple myeloma.

However, the optimal dosing interval for zoledronic acid is unknown and based on prior studies and empiricism it is administered monthly along with anti-cancer treatments.

In this trial, over 1800 breast cancer, prostate cancer and multiple myeloma patients with bone metastases were randomized to the standard dosing interval of monthly zoledronic acid versus every 3-months zoledronic acid for a duration of two years.

The results overall, and in each specific disease site, show that giving zoledronic acid once every 3-months as opposed to monthly did not result in any increase in skeletal-related
events.

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Incidence of Metastatic Prostate Cancer at Diagnosis Rises in US

MedicalResearch.com Interview with:

Dr. Jim C. Hu MD MPH Professor of Urology Weill Cornell Medicine

Dr. Jim Hu

Dr. Jim C. Hu MD MPH
Professor of Urology
Weill Cornell Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The most significant finding from our population based study is that after years of decline following the introduction of PSA screening, we see a rise in the incidence of metastatic prostate cancer at diagnosis among men aged 75 years and older. This is concerning in light of recent criticisms and guidelines against PSA testing. For instance, in 2008, the US Preventative Services Task Force recommended against PSA testing in this age group, and in our study, we see the incidence of metastasis at diagnosis rising in 2012 and 2013.

This is significant because there is no cure for men with metastatic prostate cancer of their disease. The traditional argument against PSA screening is that it leads to over-diagnosis and over-treatment of prostate cancer. However, we currently do not have a better test for diagnosing prostate cancers before it has spread beyond the prostate and metastasized. Remarkably, when Ben Stiller shared his personal use of PSA testing in his mid to late 40’s and how this led to a detection of intermediate risk prostate cancer that led him to surgery and cure, others criticized him for sharing his story.

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IL-33 May Be First Stand Alone Biomarker of Prostate Cancer Recurrence

MedicalResearch.com Interview with:
Iryna Saranchova MD
PhD candidate
Michael Smith Laboratories
Vancouver, BC

MedicalResearch.com: What is the background for this study?

• The immune system is efficient at identifying and halting the tumour emergence at early stages. However, when metastatic (sufficient to cause death) tumour appears, the immune system is no longer able to recognize the cancer cells and control their growth and spread.
• Recent studies of solid cancers have shown considerable heterogeneity between different tumour types and several lines of evidence suggest that tumours are not only heterogeneous, but they constantly evolve during the disease progression and this often hampers the existing treatment methods.
• It means that it is important to consider each patient’s mutational changes accumulated over time in antecedent primary, metastatic lesions and/or local recurrences. This approach will help to understand the mechanism of tumour development, create a background for specific treatment modality and prevent therapeutic failure with consequent systemic relapse of the disease
• Therefore, in our project we were aiming to find possible immune markers of tumour transition from the primary stage to its metastatic form. For this purpose, we selected a special study model: two pairs of separate mouse tumour cell lines, where metastatic cells arose from the initial primary tumour.

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Scaffold Can Potentially Deliver Therapeutic miRNA To Decrease Breast Cancer Metastases

MedicalResearch.com Interview with:

Natalie Artzi PhD principal research scientist MIT's Institute for Medical Engineering and Science (IMES) and Assistant professor of medicine Brigham and Women's Hospital And co-authors: Avital Gilam, João Conde, Daphna Weissglas-Volkov, Nuria Oliva Eitan Friedman, Noam Shomron

Dr. Natalie Artzi

Natalie Artzi PhD
principal research scientist
MIT’s Institute for Medical Engineering and Science and
Assistant professor of medicine
Brigham and Women’s Hospital
With co-authors:
Avital Gilam, João Conde, Daphna Weissglas-Volkov, Nuria Oliva, Eitan Friedman, Noam Shomron

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Metastases are the primary cause for mortality in breast cancer, the most common cancer in women regardless of ethnicity. Recent studies show that germline sequence variants, such as single-nucleotide polymorphisms (SNPs) in miRNA-binding sites, can disrupt the downregulation by miRNAs, with a profound effect on gene expression levels and consequentially on the phenotype, including increased risk for cancer.

In the current study, we aimed to determine the potential effect of SNPs within miRNA-binding sites on metastatic breast cancer progression and their potential use as suppression targets to prevent metastasis.

Our collaborators at Tel-Aviv Universityin a research led by Dr. Noam Shomron found that the SNP, rs1071738, located in a target site for miR-96 and miR-182 on the 3’-UTR of the PALLD gene, encodes the Palladin actin-associated protein, which is a documented player in breast cancer motility. In vitro experiments revealed a functional downregulation of Palladin levels by miR-96 and miR-182, which subsequently reduces migration and invasion abilities of breast cancer cells.

My lab then showed in an in vivo experiment that the use of nanoparticles embedded in a hydrogel scaffold as a miRNA delivery vehicle enables an efficient and specific delivery of miR-96/miR-182 directly to breast tumours, which results in marked reduction of breast cancer metastasis. We then proceeded to study the effect of combination therapy in which we will use a chemotherapy drug to shrink the primary tumor and the miRNAs to prevent metastasis. The intercalation of a chemotherapy drug, cisplatin, to the miR-conjugated nanoparticles further improved the effect, leading to significant reduction in both primary tumour growth and metastasis.

Our study highlights the therapeutic potential of miRNAs, and specifically miR-96 and miR-182, and support the importance of Palladin regulation in breast cancer metastasis.

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Lymph Node Cancer Metastases Do Not Require Growth of New Blood Vessels

Timothy P. Padera, PhD Edwin L. Steele Laboratories Department of Radiation Oncology MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114MedicalResearch.com Interview with:
Timothy P. Padera, PhD
Edwin L. Steele Laboratories
Department of Radiation Oncology
MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School
Boston, Massachusetts 02114

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Padera: Systemic therapy benefits cancer patients with lymph node metastases; however all phase III clinical trials to date of antiangiogenic therapy have failed in the adjuvant setting. We have previously reported the lack of efficacy of antiangiogenic therapies in pre-clinical models of spontaneous lymphatic metastasis, however there were no mechanistic data to explain these observations. Here, we developed a novel chronic lymph node window model to facilitate new discoveries in the mechanisms of growth and spread of lymph node metastases. Our new data provide pre-clinical evidence along with supporting clinical evidence that angiogenesis does not occur in the growth of metastatic lesions in the lymph node. These results reveal a mechanism of treatment resistance to antiangiogenic therapy in adjuvant setting, particularly those involving lymph node metastases.

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Understanding Leader Cells In Cell Migration

MedicalResearch.com Interview with:
Dr. Pak Kin Wong Ph.D.
Aerospace& Mechanical Engineering Department Biomedical Engineering and Bio5 Institute
The University of Arizona

Medical Research: What is the background for this study? What are the main findings?

Response: Collective cell migration is central to various (patho)physiological processes, such as tissue development, regeneration, and cancer metastasis. At the onset of the process, a subset of cells acquires distinct leader cell phenotypes in the initially homogeneous population and leads the migration. However, how leader cells are initiated among the initial homogeneous population and how leader cell density is regulated during collective migration remain unknown. In this study, we demonstrate the formation of leader cells is regulated dynamically by Dll4 signaling through Notch1 and cellular stress near the leading edge. Our finding provides a molecular basis for the stochastic emergence of leader cells, a process originally considered random.

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