BARIATRIC SURGERY

Association of bariatric surgery with cancer risk and mortality in adults with obesity

A recent study demonstrated that, among adults with obesity, weight loss with bariatric surgery was associated with a 32 percent lower risk of developing cancer and a 48 percent lower risk of cancer-related death versus adults who did not have the surgery (JAMA 2022; doi:10.1001/jama.2022.9009). SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) is a matched-cohort study that included more than 30,000 patients. A group of 5,053 adult patients with obesity who had bariatric surgery between 2004 and 2017 were matched 1:5 to a control group of 25,265 patients who did not have surgery for their obesity. After 10 years, 2.9 percent of patients in the bariatric surgery group and 4.9 percent of patients in the non-surgical group developed an obesity-associated cancer. In the same period, 0.8 percent of patients in the surgery group and 1.4 percent of patients in the non-surgical group died from cancer. "Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality," the study authors concluded.

AUTHOR COMMENTARY: "Based on the magnitude of benefit shown in our study, weight-loss surgery can be considered in addition to other interventions that can help prevent cancer and reduce mortality," said study author Jame Abraham, MD, at the Cleveland Clinic, in a statement. "Further research needs to be done to understand the underlying mechanisms responsible for reduced cancer risk following bariatric surgery."

PROSTATE CANCER

A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60

A recent study suggests that mitochondrial unfolded protein response-a unique longevity function of mitochondria-could be a new target for the treatment and management of metastatic, resistant, or recurrent prostate cancer (J Clin Invest 2022; doi: 10.1172/JCI149906). Current therapeutic options initially reduce tumor burden; however, disease recurrence is likely. The researchers determined that two key components of the mitochondrial unfolded protein response were necessary for the development of advanced prostate cancer: the heat shock protein 60 (HSP60), a mitochondrial chaperonin, and caseinolytic protease (ClpP), a mitochondrial protease. This study also uncovered a novel mitochondrial unfolded protein response inhibitor, DCEM1, which hampers HSP60's interactions with ClpP in prostate cancer cells and tumors. The study authors showed that this inhibition of HSP60-ClpP interaction impeded the development of resistant or aggressive disease. Using DCEM1 to disrupt the interactions between HSP60 and ClpP interferes with survival signaling and triggers metabolic stress, which results in the death of prostate cancer cells, according to their findings. "Disruption of HSP60-ClpP interaction by UPRmt inhibitor triggered metabolic stress and impeded prostate cancer promoting signaling. Treatment with UPRmt inhibitor, or genetic ablation of Hsp60, inhibited prostate cancer growth and progression," the study authors concluded. "Together, our findings identify that HSP60-ClpP mediated UPRmt is essential for prostate tumorigenesis and HSP60-ClpP interaction represents a therapeutic vulnerability in prostate cancer."

AUTHOR COMMENTARY: "The HSP60-mediated chaperonin system facilitates protein folding, whereas ClpP protease degrades unfolded protein to maintain mitochondrial protein homeostasis, which is critically required for cancer cell survival and growth," stated Dhyan Chandra, PhD, from the Roswell Park Comprehensive Cancer Center. "This suggests that a drug that interferes with the interaction of HSP60 and ClpP will disrupt cancer cell survival and block the growth and progression of prostate cancer. This study provides strong evidence for developing a novel drug for the treatment of metastatic and resistant prostate cancer. Since the current androgen deprivation and taxane-based therapies are not effective, these findings provide alternative treatment approaches for prostate cancer that do not rely on androgen receptor signaling axis."

IMMUNOTHERAPY

Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

A novel strategy has been identified by researchers to reduce immune-related adverse events caused by immunotherapy treatment by targeting the cytokine interleukin-6 (IL-6). The recently published study is a proof of concept for the combination of immune checkpoint blockade and cytokine blockers to selectively inhibit inflammatory autoimmune responses (Cancer Cell 2022;40(5):509-523.e6). While immunotherapy has been practice-changing for many different cancer types, it is also associated with high toxicity rates that can impact quality of life and even lead to treatment discontinuation in some cases. Immune-related enterocolitis (irEC), an inflammatory bowel condition, is a common and serious complication. In this translational study, the researchers analyzed patient tissue, preclinical models, and retrospective data to determine how the IL-6 T helper 17 (Th17) cell pathway contributes to toxicity and can be inhibited to separate the inflammatory autoimmune response from the antitumor immune response. Comprehensive immune profiling of matched samples of irEC tissue and normal tissue from patients treated with immune checkpoint blockade showed distinct immune signatures in the inflamed tissue-where IL-6 and Th17 were upregulated-versus normal tissue. The researchers also observed that the IL-6 gene signature was upregulated in patients whose tumors did not respond to immunotherapy, but the increased levels were not seen in responders. The study authors used several preclinical models to evaluate the effect of an IL-6 blockade on autoimmunity and on response to anti-CTLA-4 therapy. The combination of an IL-6 blocker with immune checkpoint inhibitor decreased experimental autoimmune encephalomyelitis symptoms and improved tumor control. This indicates, they noted, that the combination could suppress inflammatory response and potentially enhance antitumor immunity. A retrospective analysis, which included 31 patients with melanoma who were treated with immune checkpoint blockade and also received an IL-6 blocker to treat inflammatory arthritis and other immune-related adverse events, was conducted to validate the findings. Patients received IL-6 blockade for a median of 3.7 months after beginning to experience side effects, and the researchers noted a 74 percent improvement in symptoms after a median of 2 months on the therapy. The best overall response rate to immune checkpoint blockade was 57.7 percent before IL-6 blockade initiation and 65.4 percent after therapy. These clinical results supported the preclinical findings that targeting IL-6 can alleviate immune-related adverse events without compromising immunotherapy's efficacy.

AUTHOR COMMENTARY: "Cytokine blockers have been well-established to block autoimmunity. The novelty of this study is bringing cytokine targeting to tumor immunity and demonstrating that autoimmunity and antitumor immunity are not necessarily overlapping immune responses, but can be decoupled at the cytokine level," according to senior author Adi Diab, MD, at The University of Texas MD Anderson Cancer Center. "IL-6 is only one cytokine, but this work offers proof of principle for taking the science to the next level by targeting multiple cytokines in a multi-layered approach."