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Loss of long non-coding RNA NXTAR in prostate cancer augments androgen receptor expression and enzalutamide resistance

A new study has identified an RNA molecule that suppresses prostate tumors (Cancer Res 2021; doi: 10.1158/0008-5472.CAN-20-3845). The scientists found that prostate cancers develop ways to shut down this RNA molecule to allow themselves to grow. According to the new research-conducted in mice implanted with human prostate tumor samples-restoring this so-called long noncoding RNA could be a new strategy to treat prostate cancer that has developed resistance to hormonal therapies. The key protein that drives prostate tumor growth, the androgen receptor, binds to testosterone and stimulates cancer growth. Studying the stretch of DNA that codes for the androgen receptor, the researchers discovered that a section of the DNA molecule next to the androgen receptor produced a molecule called a long noncoding RNA. They found that this long noncoding RNA plays a key role in regulating the androgen receptor and vice versa. Because of its position next to the androgen receptor in the genome, the researchers dubbed it NXTAR (next to androgen receptor). The researchers discovered NXTAR by using a drug that suppresses the androgen receptor. When the androgen receptor is suppressed, NXTAR starts to appear. The drug, called (R)-9b, was developed to attack a different aspect of prostate cancer biology, knocking down expression of the androgen receptor overall rather than just blocking its ability to bind to testosterone or reducing overall testosterone levels in the body, as do currently approved drugs. But in this study, (R)-9b ended up serving as a tool to reveal the presence and role of NXTAR. Studying human prostate tumor samples implanted in mice, the researchers showed that restoring NXTAR expression caused the tumors to shrink. They also showed that they didn't need the entire long noncoding RNA to achieve this effect. One small, key section of the NXTAR molecule is sufficient for shutting down the androgen receptor.



DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma

An experimental drug enhanced the benefit of an immunotherapy to fight pancreatic cancer in mice by increasing the number of immune cells in the immediate vicinity of the tumor, leading to a reduction in tumor growth and, in some mice, eliminating their cancer (J Immunother Cancer 2021; doi: 10.1136/jitc-2021-002837). The findings provide early evidence that the drug could jump-start an immune response against pancreatic cancer, a disease that has so far been resistant to immunotherapy. The data come from experiments of BXCL701, an experimental dipeptidyl peptidase (DPP). The microenvironment surrounding most pancreatic tumors is very effective at blocking immune system attacks, so researchers turned to BXCL701, an experimental oral DPP inhibitor. The drug candidate has been observed to help boost the effectiveness of immunotherapies in some early-phase clinical trials. Scientists studied two sets of mice that were injected with cells that closely mimic human pancreatic cancer. The mice were then given the immunotherapy, along with BXCL701. The combination of therapies enhanced immunotherapy effectiveness by boosting two key immune system components: T cells and natural killer cells. Investigators found that natural killer cells contributed importantly to longer survival. Natural killer cells play a key role in an immune defense against cancer in two ways: they recognize and kill cancer cells directly, similar to T cells, but also release small signaling molecules that can influence and regulate other parts of the immune system. Investigators believe that, based on this and other research, many immune cell types work together to keep cancer cells at bay.



The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases

Treatment with arginine, one of the amino-acid building blocks of proteins, enhanced the effectiveness of radiation therapy in cancer patients with brain metastases, in a proof-of-concept, randomized clinical trial (Sci Adv 2021; doi: 10.1126/sciadv.abg1964). The study reported the results of administering arginine, which can be delivered in oral form, prior to standard radiation therapy in 31 patients who had brain metastases. Nearly 78 percent had a complete or partial response in their brain tumors over the follow-up period of up to 4 years, while only 22 percent of the 32 patients who received a placebo prior to radiotherapy had such a response. The trial was designed to gauge the effectiveness of arginine as a "radiosensitizer" that enhances the effects of radiation treatment. However, the results, and arginine's apparent mechanism of action, suggest that the amino acid might be useful more broadly as an anticancer therapy. Arginine, also called L-arginine, is inexpensive and widely available, generally considered safe, and can get relatively easily from the bloodstream into the brain. The idea of using it to treat cancer arose from observations that tumors often aid their own survival by producing high levels of the related molecule nitric oxide (NO). The latter regulates multiple processes in the body, including the flow of blood through blood vessels, and tumors cells often make more NO by upregulating their production of special enzymes called NO synthases, which synthesize NO from arginine. Reducing NO production is one possible way of exploiting tumors' dependence on this molecule, but hasn't worked well, in part because of adverse side effects. The investigators hypothesized that boosting NO production instead-by adding its precursor arginine-might be beneficial because, while tumors can use NO to aid their growth and survival, they must keep its production below certain limits. Overloading a high-NO tumor with much more NO prior to radiation treatment could weaken the tumor's ability to repair radiation-induced DNA damage-and indeed preclinical experiments in mice confirmed this effect. In the clinical trial, patients were treated with high-dose arginine or placebo oral suspensions an hour before radiotherapy for their brain metastases. Six months after their courses of radiotherapy, 82 percent of the arginine group had improvement, or at least no worsening, of their neurological symptoms, compared with 20 percent in the placebo group. Most of the arginine-treated patients who died during the study did so because of their cancers' spread elsewhere in the body. Moreover, although metastatic cancer usually has a dire prognosis, there were some arginine-treated patients whose tumors in and outside the brain disappeared, suggesting the possibility of cures. Evidence from this study and prior research also suggests that arginine can not only directly hobble tumor cells, but also boost the activity of antitumor immune cells. The promising results have prompted the team to start and plan further studies of arginine on its own or in combination with other anticancer treatments.


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