City of Hope Preclinical Study Uncovers Two Proteins’ Crucial Role in Causing Cancer Cell Growth February 5, 2024
Introduction:
(Eurekalert) Scientists at City of Hope®, one of the largest cancer research and treatment organizations in the United States, have discovered a new cellular mechanism that plays an important role in cancer cells’ ability to cause disease. The study was published in Nature Structural & Molecular Biology today.
A team led by Chun-Wei (David) Chen, Ph.D., an associate professor of systems biology at City of Hope, pinpointed two cell-surface proteins, integrin αV and β5, that partner to spur cancer cell growth. The researchers next identified a region of integrin αV called the β-propeller domain that controls interaction between the two proteins.
Blending laboratory experiments with computer simulations, Chen’s team created a powerful digital application of CRISPR gene-tiling technology to uncover potential cancer medicines that precisely target the β-propeller domain.
After identifying the chemical compound Cpd_AV2 as a strong candidate, the team applied this compound to human cancer cells in the laboratory. Integrin αV and β5 rapidly separated, dissolving communication between the two proteins and causing cellular death, effectively halting growth in cancer cell lines.
Clinically, the researchers found integrin αV overexpression in multiple cancer types, highlighting integrin αV’s lead role in cancer progression. High levels of integrin αV were also associated with a poor prognosis in 3,700 patients with cancers of the breast, pancreas, liver, lung and brain.
A multidisciplinary research team at Vanderbilt University and Vanderbilt University Medical Center has discovered a new way to kill a tumor by disrupting its acidic "microenvironment" without harming normal tissue.
The target of this unorthodox approach is hydroxyapatite (HAP), a naturally occurring mineral that is a major component of bone and teeth but is also produced by some tumors.
In the extracellular microenvironment that surrounds and nourishes tumors, HAP crystals can enhance tumor cell proliferation, progression, and migration (metastasis). However, HAP is absent in normal soft tissue, making it an attractive target for cancer imaging and treatment.
Using various molecular analytical methods, the researchers identified and synthesized a nanoparticle that, when delivered via an injectable solution called NSPS, chelated or bound to calcium on tumor-associated HAP crystals, causing them to dissolve.
A multi-institutional team of Chinese microbiologists and pharmacologists has developed a novel way to fight cancerous tumors. Called ONCOTECH, it combines oncolytic virotherapy and adoptive T cell therapy for treatment of patients with cancerous tumors. The study is published in the journal Nature Biotechnology.
Oncolytic virotherapy involves the use of one or more viruses that work to selectively infect and kill tumor cells, while simultaneously stimulating the immune system to attack the same tumors. Adoptive T cell therapy is a cancer-fighting technique that involves the use of engineered T cells programmed to recognize and attack tumor cells.
In this new study, the researchers developed a therapy approach that involves both techniques. Called ONCOTECH, it is developed to physically attach oncolytic viruses onto T cell surfaces by using engineered biological membranes with T cell-specific antigens, resulting in the use of oncolytic adenoviruses (OAs). It also involves the encoding of a CRISPR–Cas9 system to target the PD-L1 gene, which is often overexpressed by tumor cells as a means to evade an immune system attack.
St. Jude Children's Research Hospital scientists have improved chimeric antigen receptor (CAR) T–cell immunotherapy for acute myeloid leukemia (AML), demonstrating better efficacy in the lab.
To overcome common problems with CAR T cells, the researchers created an additional means for the therapy to find and eliminate cancer cells, using a small peptide. The study also showed how a computational approach incorporating AlphaFold predicted protein models could help understand how structure impacts antigen recognition and therapy efficacy.
Their findings are published in the journal Cell Reports Medicine.
Immunotherapy that reprograms a patient's own immune cells to target a cancer-specific protein, CAR T–cell therapy, has shown success in treating some relapsed leukemias. However, sometimes the treatment is unsuccessful because cancer cells that do not have the targeted protein can still grow, escaping the therapy and causing a relapse. The relapse rate for AML is high, leading to a poor prognosis for the disease overall.
A new, cutting-edge study from the University of Ottawa (uOttawa) has found vanoxerine, a drug initially developed for the treatment of cocaine addiction, could impede advanced colorectal cancer stem cells by essentially re-wiring critical gene networks.
This new research published in Nature Cancer led by Dr. Yannick Benoit, Principal Investigator and Associate Professor in the Department of Cellular and Molecular Medicine (Faculty of Medicine) at uOttawa, has revealed that vanoxerine plays an entirely unexpected mechanism in cancer.
The investigators observed that vanoxerine packs a powerful punch when suppressing cancer stem cell activity in colon cancer patients' tissues and in tumors implanted in laboratory animals. It interferes with a protein that transports dopamine, the brain chemical involved in sensations of pleasure and reward, and represses an enzyme dubbed G9a in colorectal tumors.
"Notably, the tumors treated with vanoxerine become more susceptible to attack by the immune system due to the reactivation of ancient viral DNA fragments accumulated in our genome throughout evolution. This finding is quite significant, considering that colorectal tumors tend to show poor response to standard immunotherapy," says Dr. Benoit, who was one of six national winners of the Gairdner Foundation's 2022 Early Career Investigator competition.
New treatment for a rare and aggressive cancer improves survival rates in breakthrough clinical trial
15 February 2024
The phase 3 clinical trial, published today in JAMA Oncology and sponsored by Polaris Pharmaceuticals, has unveiled a breakthrough in the treatment of malignant pleural mesothelioma (MPM), a rare and often rapidly fatal form of cancer associated with exposure to asbestos and which has limited therapeutic options. The trial found that a combination treatment of traditional chemotherapy with a new drug, ADI-PEG20, increased the median survival of participants by 1.6 months, and quadrupled the survival at 36 months, compared to placebo-chemotherapy.
The findings are significant, as MPM has one of the lowest 5-year survival rates of any solid cancer of around 5-10%. This innovative approach marks the first successful combination of chemotherapy with a drug that targets cancer's metabolism developed for this disease in 20 years.
Researchers Characterize the Immune Landscape in Cancer February 14, 2024
Introduction:
(Eurekalert) New York, NY [February 14, 2024]—Researchers from the Icahn School of Medicine at Mount Sinai, in collaboration with the Clinical Proteomic Tumor Analysis Consortium of the National Institutes of Health, The University of Texas MD Anderson Cancer Center, Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and others, have unveiled a detailed understanding of immune responses in cancer, marking a significant development in the field. The findings were published in the February 14 online issue of Cell [DOI: 10.1016/j.cell.2024.01.027].
Utilizing data from more than 1,000 tumors across 10 different cancers, the study is the first to integrate DNA, RNA, and proteomics (the study of proteins), revealing the complex interplay of immune cells in tumors. The data came from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), a program under the National Cancer Institute.
"We aimed to improve our understanding of the mechanisms underlying the functional impairment of immune response in tumors. By closely examining genes and proteins in the tumor tissues, we discovered various patterns in immune activation and suppression," says Pei Wang, PhD, Professor of Genetics and Genomic Sciences at Icahn Mount Sinai, and the lead-corresponding author on the paper. "Our goal in unraveling these diverse immune subtypes is to help clinicians identify patient groups more responsive to immunotherapy. Revealing the specific pathways and cellular switches for each subtype can also spark new and creative ways to develop treatments."
"Each type of immune response was linked to changes in gene functions, such as how genes are modified, the messages they send, and the proteins they produce. By providing a comprehensive molecular fingerprint of the immune response in cancer, this study is expected to facilitate the development of future immunotherapy strategies," says Francesca Petralia, PhD, Assistant Professor of Genetics and Genomic Sciences at Icahn Mount Sinai, and co-corresponding author on the paper.
A key finding was that among seven subtypes identified through advanced statistical models, five included tumors from ten different types of cancer, suggesting shared immune responses across these tumors.
Lung cancer is one of the most common cancers and has one of the lowest survival rates in the world. Cytokines, which are small signaling proteins, such as interleukin-12 (IL-12), have demonstrated considerable potential as robust tumor suppressors. However, their applications are limited due to a multitude of severe side effects.
