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Discovery of a First-in-Class Potent Small Molecule Antagonist Against the Adrenomedullin-2 Receptor

A new drug that could improve life expectancy and quality for patients with hard-to-treat cancers, such as pancreatic cancer and relapsed breast cancer, has been invented by scientists (ACS Pharmacol Transl Sci 2020; The team made the discovery after examining a hormone, called adrenomedullin, which controls blood pressure and other vital body processes, but also stimulates the growth and spread of cancer. Using novel drug molecules, known as adrenomedullin-2 receptor antagonists, the scientists discovered a way to block the way that adrenomedullin is used in communication with cancer cells, without affecting the way it helps to regulate vital processes in the body such as blood pressure. Findings of the pioneering study show the new drug molecules have a positive effect in the treatment of pancreatic cancer in mice models. Tumors did not grow as fast, which provides evidence to suggest life expectancy would be extended. The compound is different from traditional therapies such as cytotoxic drugs and radiotherapy because it targets a very small number of cells and does not damage healthy cells in the body. It is hoped this will improve quality of life for patients undergoing treatment.



Combined Gas Embolization and Chemotherapy Can Result in Complete Tumor Regression in a Murine Hepatocellular Carcinoma Model

Hepatocellular carcinoma is a stubborn form of cancer with few treatments and a high mortality rate. The common treatment, transarterial chemoembolization, is invasive and too imprecise to be a local drug delivery method. Aiming to increase the precision, researchers created a combination treatment that involves vaporizing tiny droplets of perfluorocarbon, a common organic material composed of carbon and fluorine that is used in pharmaceuticals, anesthetics, and industrial fluids (APL Bioeng 2020; The study tested gas embolization alone and in combination with two common cancer drugs, doxorubicin (DOX) and tirapazamine. Gas embolization stops blood flow to the tumor, and it was highly effective used in combination with DOX. In the gas embolization method, perfluorocarbon liquid is administered intravenously, and it interacts with DOX that has been administered in the body. DOX binds to the surface of the droplets of liquid, which are small enough to travel through capillaries and do not cause blood vessel blockage until they are vaporized, so treatment can be applied at the specific site of the tumor. To turn these tiny liquid droplets into microbubbles and cut off the blood flow to the tumor, ultrasound is applied from outside the body. The fluid mechanical interface of the droplet focuses the ultrasound in a cavitation-like event, in which gas bubbles inside the liquid droplet grow due to a drop in pressure, until the droplet turns completely into microbubbles. The drug DOX binds to the shell of the droplet, and the medicine becomes available to diffuse into the tumor, while the microbubbles cut off blood supply to the tumor. The combination of gas embolization and DOX was so effective that, on average, tumors shrank to 2.9 percent of their initial size, while using DOX alone slowed tumor growth but still allowed them to grow to 300 percent of their initial size.



Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small Cell Lung Cancer

A targeted therapy called capmatinib can provide significant benefits to patients who have advanced lung cancer with specific gene mutations, according to recently published results from a phase II clinical trial (N Engl J Med 2020; doi: 10.1056/NEJMoa2002787). A protein called MET affects a wide range of processes within cells, and alterations that activate the MET gene, which codes for this protein, have been implicated in many cancers. MET can be activated by a variety of mechanisms. Multiples copies of the MET gene, called MET amplification, occur in 1-6 percent of patients with non-small cell lung cancer (NSCLC). MET exon 14 skipping mutations, which cause deletion of a region called exon 14 in the expressed protein, occur in approximately 3-4 percent of patients with NSCLC and are associated with a poor prognosis. Capmatinib is a highly potent and selective inhibitor of MET. Now researchers report results from the phase II GEOMETRY mono-1 study, which investigated the activity of capmatinib in 364 patients with advanced NSCLC with MET exon 14 skipping mutations or MET amplification. Results from this study were the basis for the FDA May 2020 approval of capmatinib for the treatment of NSCLC patients with MET exon 14 skipping. In patients with MET exon 14 skipping mutations, capmatinib had a very high response rate (68%) when used as the first line of treatment, and an excellent response rate (41%) when used after patients had been treated with other therapies, such as chemotherapy and immunotherapy. Among patients with MET amplification with at least 10 copies of the gene, capmatinib had a response rate of 40 percent when used as a first-line treatment and a response rate of 29 percent when used after other treatments. The drug had limited effectiveness in patients with a lower level of MET amplification. The results indicate that capmatinib may be an especially effective treatment for patients who have NSCLC with MET exon 14 skipping mutations and who have not been treated previously.



Determining the Thermal Characteristics of Breast Cancer Based on High-Resolution Infrared Imaging, 3D Breast Scans, and Magnetic Resonance Imaging

New research takes a critical step toward making digital infrared thermal imaging more useful for monitoring breast cancer (Sci Rep 2020; The research team used a high-resolution infrared camera, clinical data from patient volunteers, 3D scanning, and computer-aided design to build a proof-of-concept computer model of the thermal properties of breast cancer. The authors said their goal is to improve digital thermal imaging as a tool for monitoring cancer and its treatment, rather than replacing cancer screening by mammograms. The research utilized thermal imaging, with the infrared camera taking images of the skin, to identify temperature changes generated by breast cancer as it induces changes to the local vasculature and cellular metabolism. The technique only shows patterns of heat and blood flow on or near the surface of breasts, however, leaving unknown information about tumor activity deeper in the breast tissue. The researchers worked to address this issue by applying engineering tools to imaging data to develop a model that quantifies the thermal characteristics of breast cancer throughout one patient's breast. The results showed a detectable temperature difference in metabolic heat generation between the patient's normal and cancerous breasts. They also noted increased perfusion rates, which is the rate of blood flow through a given volume, in the affected breast. The researchers cautioned that the model cannot be applied to all types of breast cancer. In addition, not all breast cancers generate sufficient heat to be detected via thermography. Now that researchers have demonstrated their computational model, they plan to develop models for the other breast cancer patients enrolled in the study.