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Mutations in RABL3 Alter KRAS Prenylation and Are Associated with Hereditary Pancreatic Cancer

Scientists studying a highly cancer-prone family have identified a rare, inherited gene mutation that dramatically raises the lifetime risk of pancreatic and other cancers (Nat Genet 2019; doi: 10.1038/s41588-019-0475-y). The discovery of the previously unknown mutation could lead to routine testing of individuals with a strong family history of pancreatic cancer to determine if they carry the mutation, occurring in the RABL3 gene. If so, they could be screened to detect pancreatic cancer in an earlier, potentially more treatable stage. The newly identified mutation in the gene RABL3 similarly increases the likelihood that cancer will develop during the person's lifetime. The RABL3 mutation was pinpointed when scientists studied a family in which there were five relatives with pancreatic cancer and multiple family members with other cancers-a pattern suggesting an inherited mutation causing predisposition to developing cancer. Researchers recapitulated the genetic mutation in large zebrafish populations and performed rapid epidemiological studies to assess the impact of the mutation on cancer risk. They found that, similar to individuals in the patient family, zebrafish carrying the RABL3 mutation had dramatically higher rates of cancer. Specifically, the researchers said the RABL3 mutation accelerates the movement of a known pancreatic cancer protein, KRAS, within the cell. This alteration facilitates the placement of KRAS in the cell membrane and triggers a series of events that promote cancerous growth. Because KRAS activity is altered in a majority of pancreatic cancers, continued study of the RABL3 mutation's impact on KRAS activity could provide important insights about pancreatic cancer development as well as a new strategy for targeted therapy, said the scientists. The researchers emphasized that the RABL3 mutation is rare in the general population, but testing for it-and potentially other mutations in the RABL3 gene-may reveal the genetic predisposition in other families with an unsolved hereditary cancer syndrome.



Proteogenomic Landscape of Squamous Cell Lung Cancer

Researchers took a closer look at squamous cell lung cancer (SCC) tumors to determine if their characteristics had an impact on patient outcomes (Nat Comm 2019; doi: 10.1038/s41467-019-11452-x). The research team performed extensive analysis on 108 SCC tumor samples that included copy number alterations, DNA mutations, RNA and protein expression patterns, and pathology. They determined that the SCC tumors could be grouped into three main subtypes based on their protein expression patterns: inflamed, redox, and mixed. The inflamed subtype accounted for 40 percent of the tumor tissue, Those samples had higher levels of proteins associated with immune cells, especially neutrophils or myeloid cells, and an active inflammatory response. Based on RNA data, the researchers discovered that the inflamed subtype also had a high proportion of other immune cells, including memory B cells and monocytes, and was associated with higher levels of PD-1 than the other two subtypes. The redox subtype was noted in 47 percent of the tumors. The specimens were characterized by higher levels of proteins that are associated with oxidation-reduction cellular signaling pathways. The redox subtype also had a higher number of genetic and chromosomal alterations that are known to be involved in SCC development. Using these data as guides, they identified new vulnerabilities that could be possible future therapeutic targets. The final subtype, the mixed group, represented 13 percent of the tumors and only displayed an increased level of four proteins. The researchers did not find any significant chromosomal alterations in this subtype, but did learn that the mixed group had more mutations in the APC gene and had a greater infiltration of stromal cells than the other subtypes. The analysis showed that the three subtypes did not correspond to better or worse patient outcomes. However, tertiary lymph node structures, more commonly found in the inflamed subtype, were associated with better outcomes.



Associations of Physical Activity With Survival and Progression in Metastatic Colorectal Cancer: Results From Cancer and Leukemia Group B (Alliance)/SWOG 80405

Patients with metastatic colorectal cancer who engaged in moderate exercise while undergoing chemotherapy tended to have delayed progression of their disease and fewer severe side effects from treatment (J Clin Oncol 2019; doi: 10.1200/JCO.19.01019). Even low-intensity exercise, such as walking 4 or more hours a week, was associated with a nearly 20 percent reduction in cancer progression or death over the course of the 6-year study. Patients participated in a phase III study of chemotherapy for advanced colorectal cancer conducted by the Alliance for Clinical Trials in Oncology and sponsored by the NCI. Within a month after beginning treatment, patients were invited to complete a questionnaire about their average physical activity over the previous 2 months. The final number of participants included 1,218 patients. While the data are significant, further research with a randomized prospective trial will help validate the results, the researchers said. Based on the patients' descriptions, researchers quantified their physical activity in terms of metabolic equivalent task (MET)-hours per week. Vigorous activity was defined as any activity requiring six or more METs, such as running, biking, tennis, skiing, or lap swimming. Non-vigorous activities included walking, climbing stairs, or yoga. Analysis of the data revealed a statistically significant difference in PFS-the length of time after the patient completed the questionnaire before the cancer progressed or the person died. The difference in PFS was almost 20 percent in favor of those who exercised more. The analysis also found that patients who engaged in 18 or more MET-hours per week of activity had a 15 percent improvement in overall survival (death from any cause) than patients who engaged in less than 3 MET-hours per week of activity. However, that difference was not statistically significant, meaning it could have resulted from chance.



Regulatable Interleukin-12 Gene Therapy in Patients With Recurrent High-Grade Glioma: Results of a Phase I Trial

A phase I clinical trial has demonstrated that a two-step gene therapy treatment was safe and effective in 31 patients with recurrent glioblastoma potentially overcoming a major hurdle that has hindered the use of systemically administered interleukin 12 (IL-12)-based regimens (Sci Transl Med 2019; doi: 10.1126/scitranslmed.aaw5680). The therapy boosted the infiltration of immune cells into tumors and showed encouraging preliminary benefits, indicating it has promise as a treatment for patients with this usually fatal disease. Studies have found that IL-12 has beneficial effects against cancer, but it cannot be administered systemically due to its unfavorable safety profile. In search of a much-needed treatment alternative, researchers developed an approach that leverages the anticancer benefits of IL-12, while limiting its toxicity. Their two-step approach (conducted after surgical removal of the tumor) involved injecting the tumor site with a viral vector that delivers the gene for IL-12, followed by oral administration of a drug candidate named veledimex that triggers the production of IL-12. In a multicenter phase I trial, the regimen boosted IL-12 production in the brains of 31 patients with recurrent glioblastoma while limiting the amount of IL-12 that entered systemic circulation. Although some patients exhibited serious side effects, they were easily reversed after discontinuing the treatment and were less severe in patients receiving lower doses of veledimex. Antitumor immune cells penetrated the tumor more effectively after treatment, and the scientists saw signs that the therapy may have boosted overall survival. Patients who received restricted doses of the corticosteroid dexamethasone throughout IL-12 treatment showed greater survival benefits, hinting that limiting corticosteroid use could maximize the benefits of IL-12 treatment and similar immunotherapies.