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NCI supports 10 New Bilateral Collaborative Research Partnerships on Cancer

, by Paul Pearlman & Sophia Michaelson

The Center for Global Health works with foreign scientific funding agencies to incentivize cooperation on work that is of importance to the American cancer research enterprise.

The Russian Federation has played a key leadership role in the global political discourse surrounding non-communicable diseases (NCDs).  In particular, they have held high-level dialogues with U.S. leaders on the sidelines of the Asia-Pacific Economic Cooperation (APEC) and have been one of the driving forces behind APEC’s Health Working Group and its focus on “NCDs throughout the life course”. This focus follows from the fact that NCDs overwhelmingly drive mortality in Russia. Similar to the U.S., premature mortality from cancers has not changed significantly over the last decade. Cancers common to Russia are similar to those in the U.S., with the exception of high lung cancer rates in Russian men and lagging lung cancer rates in Russian women.

Recognizing that enhanced cooperative biomedical research on cancer would be of mutual benefit to the U.S. and the Russian Federation, the NCI Director and the President of the Russian Basic Research Foundation (RFBR) signed a Memorandum of Understanding (MOU) in October 2013 and a delegation from the NCI met with RFBR in November 2013 to initiate a joint grants program. A Joint Working Group, made up of members from both NCI and RFBR, developed strategic plans for collaboration, review, and clearance of proposed projects. Both the NIH and RFBR allocated funds to support joint activities pursued under this program.

The ultimate purpose of the U.S.-Russia Bilateral Collaborative Research Partnerships on Cancer program is to stimulate collaborative basic, translational, and clinical research between U.S.-based researchers and Russian researchers in the areas of cancer biology, prevention, early detection, diagnosis, and treatment; as well as the physical and chemical sciences and engineering in cancer biology, nanotechnology, and radiation epidemiology.  

NCI is proud to announce the projects supported by this collaborative work.

Andrei Holodny and Kyung Peck, from Memorial Sloan Kettering Cancer Center, have partnered with Igor Pronin, from the Burdenko Neursurgery Research Institute, to work on Identification of Essential Areas of the Brain in Pre-Operative Brain Tumor Patients Using BOLD fMRI and Independent Physiological Parameters.  Each year, 210,000 new cases of primary or metastatic brain tumors are diagnosed in the U.S. and 65,000 in Russia. Neurosurgical resection remains the mainstay of the treatment of brain tumors, which requires maximizing the resection of the tumor while avoiding important adjacent eloquent cortices and devastating neurological consequences. These are the same neurosurgical challenges faced by both countries. Blood oxygen level dependent (BOLD) functional MRI may guide the resection of tumors adjacent to important areas of the brain such as eloquent cortices; however, there is a significant limitation in the accuracy of BOLD fMRI for areas adjacent to brain tumors. This study will explore an independent measurement of cerebrovascular reactivity through breath-hold MRI into the BOLD fMRI analysis to overcome the false negative activation due to neurovascular uncoupling by tumor neovasculature.

Stephen Johnston, from Arizona State University, has partnered with Andrei Chapoval, from Altai State University to investigate Immunosignatures to Distinguish Breast Cancer Subtypes and Cancer Recurrence. This project employs an innovative technology to test blood samples in order to diagnose the subtype of a patient’s breast cancer (luminal A, luminal B, HER2-enriched or basal) and to monitor her for recurrence of the disease. This technique can be applied to dried blood samples. If successfully developed, the technique is likely to find its most immediate application in settings where the current diagnostic modalities for breast cancer, which rely on imaging and on molecular characterization of excised tumor tissue, are not available. However, if proven sufficiently reliable, it could complement or even displace these current technologies anywhere 

Tayyaba Hasan, from Massachusetts General Hospital, has partnered with Ilya Turchin, from the Institute of Applied Physics of the Russian Academy of Sciences to work on Optical Imaging Guided Resection and Photodynamic Therapy of Glioma with Targeted Photoactivable Agents. Gliomas have a very poor survival rate, even with aggressive surgical resection. Fluorescence-guided resection followed by the combination of photodynamic therapy at the margins and anti-EGFR therapies has improved survival somewhat. In recent studies, a 28% increase in two-year survival has been noticed. In this collaboration, the team from Massachusetts General Hospital proposes to fabricate and test a nanoparticle method for delivering a combination of photodynamic therapy and receptor tyrosine kinase inhibitor therapy to improve upon these results.

Vasily Studitsky, from Fox Chase Cancer Center, has partnered with Alexey Feofanov, from Lomonosov Moscow State University to investigate Mechanisms of PARP-1 Interaction with Chromatin. Human PARP-1 is involved in three normal cellular activities, chromatin reorganization, transcription, and DNA repair. PARP-1 is a multi-domain protein that serves as the main sensor of single and double DNA strand breaks, and is one of six enzymes required for the DNA repair process. Overexpression of PARP-1 is a marker for aggressive cancers and, therefore, also an important cancer drug target. Drs. Studitsky and Feofanov are pursuing a systematic analysis of the effects of the wild type and mutant PARP-1 variants on the structure and transcription of different nucleosomal templates to obtain a detailed description of PARP-1-dependent processes.

George Schade, from University of Washington, has partnered with Vera Khokhlova, from Lomonosov Moscow State University to work on Focal Therapy of Prostate Cancer using Non-Thermal Tumor Ablation with Focused Ultrasound. In this project, the investigators will design, develop, and test the performance of a device based on an alternative high-intensity focused ultrasound (HIFU) approach, termed boiling histotripsy (BH), first using in ex-vivo models of canine and human prostatic tissues, and then in a preclinical trial of canine prostate cancer to assess safety and efficacy. Instead of the long exposures used in HIFU, BH ultrasound pulses of high intensity and very short duration are used to impart focused mechanical shocks to fractionate targeted tissue into subcellular components, under real-time ultrasound imaging feedback. As such, BH is both targeted and not a thermal approach, so it does not carry the same risks for collateral damage as those associated with thermal ablation.

Eduard Chekmenev, from Vanderbilt University, has partnered with Igor Koptyug, from the International Tomography Center of the Russian Academy of Sciences to work on Magnetic Resonance Spectroscopy and Molecular Imaging of Metabolic Pathways in Cancer. Hyperpolarized magnetic resonance spectroscopic imaging (HP MRI or MRSI) is an emerging field that uses nuclei instead of protons. Hyperpolarization increases the nuclear spin alignment by several orders of magnitude, which enhances the signal exponentially. The gain in sensitivity allows detection of metabolites and molecular probes at low concentrations. Drs. Chekmenev and Koptyug and their teams will generate the molecular precursors for production of hyperpolarized 1-13C-pyruvate, to be used to image lactate levels in tumors.

Wilma Hofmann, from SUNY Buffalo, has partnered with Ivan Vorobjev, from Lomonosov Moscow State University to investigate the Role of Myosin IC in Prostate Cancer Metastasis. Drs. Hofmann and Vorobjev propose to study the unconventional molecular motor, myosin IC isoform A, in prostate cancer, and its role in metastasis. Dr. Hofmann recently discovered myosin IC isoform A, which is minimally expressed in most normal tissues with the exceptions of pancreatic, kidney, adrenal gland and a subset of adipose tissues. However, in human metastatic prostate cancer myosin IC isoform A is highly expressed at both the mRNA and protein level. Preliminary data presented in this application suggests the involvement of myosin isoform A in exosome secretions, and an epigenetic transmission of myosin IC isoform A’s expression from invasive to noninvasive cells.

Alexander Kabanov, from the University of North Carolina, has partnered with Natalia Klyachko, from Lomonosov Moscow State University to develop and study Targeted Magneto-Mechanic Nanotherapeutics for Cancer. Triggered activation of therapeutics at the site of action is a goal of many treatment strategies.; however, many of these strategies may not be as robust as needed to be efficacious. Using their joint expertise in nanotechnology, drug delivery, and physics, Drs. Kabanov and Klyachko discovered a new mechanism of toxicity for small magnetic nanoparticles using non-heating, super-low frequency alternating magnetic fields to stimulate realignment of these nanoparticles, enabling them to mechanically disrupt the cytoskeletons of cancer cells. They have demonstrated in previous publications similar effects for several magnetic nanoparticles in cell models. In this work, the investigators will establish feasibility for this magneto-mechanical, anti-tumor effect in an animal model for the first time, with a focus on breast cancer, and will then optimize the anti-cancer effects in vitro and in vivo using a new field generator developed by the Russian team.

Mikhail Nikiforov, from Roswell Park Cancer Institute, has partnered with Sophia Georgieva, from the Institute of Gene Biology of the Russian Academy of Sciences, to investigate the Inhibition of MYC Interactions with Chromatin-remodeling Factors as a Novel Anti-melanoma Strategy. Metastatic melanoma is incurable, has a short survival time, and therapeutic agents targeting it are an unmet need. The MYC protein is overexpressed in many aggressive cancers, including malignant melanoma. The MYC protein is also essential for the growth of melanoma in mouse models. Dr. Nikiforov has identified a small molecule inhibitor, AM7, which inhibits c-MYC and decreases tumor growth in mice without noticeable side effects. Preliminary data demonstrates that AM7 does not decrease c-MYC mRNA or protein levels, but inhibits the interaction between c-MYC and interacts with at least one component of the chromatin-remodeling complex SWI/SNF. The investigators will test whether AM7 suppresses melanoma maintenance via disruption of c-MYC interactions with certain SWI/SNF complexes.

Peter Kharchenko and Catherine Wu, from Harvard Medical School, has partnered with Anna Gorbunova, from Saint-Petersburg State University to perform a Single-cell Analysis of Tumor-microenvironment Interactions in Follicular Lymphoma. Follicular Lymphoma (FL) tumors have a complex organization of transformed B cells and other non-malignant cells that compose a tumor microenvironment (TME). The composition of this TME appears to be associated with disease prognosis, but the mechanisms and cellular interactions contributing to it are unclear. This work will focus on identification of early molecular interactions between the FL cells and the TME. To elucidate these interactions, Drs. Kharchenko, Wu, and Gorbunova will characterize the cell type composition and transcriptional state heterogeneity of FL tumors and their microenvironment using single-cell RNA-seq; identify the main modes of transcriptional co-variation between tumors and their microenvironment; and evaluate the association of transcriptional variation of different cell types with clinical outcome in FL from a biobank of FL samples.

These exploratory projects will be conducted over the next three years; however, the scientific exchanges between researchers in the U.S. and the Russian Federation are sure to contribute to our most fundamental understanding of cancer biology, and how to combat cancers at the point-of-care.