As we are saying goodbye to summer season, benefit from the collection of articles handpicked by the editors of the AACR journals from the August points. Highlights embrace a chemotherapy mixture routine for delicate tissue sarcoma, a research on the affect of visceral adipose tissue on most cancers growth, the usage of bronchoalveolar lavage for genomic profiling of lung most cancers, and extra. As all the time, the chosen articles are freely accessible for a restricted time.
Journal: Most cancers Immunology Analysis
Whereas adoptive mobile remedy (ACT) has led to sturdy responses in some sufferers, its extremely individualized design requires an extended wait time than most different most cancers remedies. Researchers are occupied with producing available “off-the-shelf” ACT that targets widespread tumor antigens, reminiscent of mutations within the p53 tumor suppressor. On this research, researchers sequenced tumors from sufferers with metastatic strong cancers to detect p53 mutations and establish tumor-infiltrating lymphocytes (TILs) that may acknowledge and react to p53 tumor antigens. They used their findings to generate a library of 39 T-cell receptors concentrating on p53 mutations that have been shared throughout 7.3 p.c of sufferers and that acknowledged tumor cells bearing p53 mutations in in vitro and in vivo fashions. Amongst 12 sufferers who have been handled with expanded p53-reactive TILs, two had partial responses. In a separate experiment, a affected person with breast most cancers was handled with ACT made up of autologous peripheral blood lymphocytes engineered to precise a T-cell receptor particular for a p53 mutant. This strategy led to enhanced immune responses and extended persistence in contrast with the TIL enlargement strategy, in addition to tumor regression that lasted for six months. The authors counsel that the p53-reactive T-cell receptors recognized on this research ought to be additional evaluated as potential remedy for sufferers with superior cancers. A associated commentary might be discovered right here.
Journal: Most cancers Epidemiology, Biomarkers, & Prevention
Weight problems will increase the danger for a number of cancers. Visceral adipose tissue (VAT) is a hormonally energetic element of fats, and its accumulation on the stomach is related to metabolic dysfunction, cardiometabolic illness, and untimely mortality. Nevertheless, its affect on most cancers growth isn’t identified. Right here, researchers examined the affiliation of belly VAT, in addition to whole fats mass, with most cancers incidence and mortality amongst white and Black people. The research included 3,017 white adults and 1,347 Black adults whose belly VAT and whole fats mass have been measured by imaging between the years 1995 and 2016. Topics have been adopted via 2017 for prognosis of invasive most cancers or cancer-related dying. The authors discovered that each VAT and whole fats mass considerably elevated most cancers incidence and that VAT considerably elevated the danger of most cancers mortality after adjustment for numerous elements. The noticed impacts of VAT and whole fats mass weren’t depending on intercourse or race. This text was highlighted within the August difficulty.
Journal: Molecular Most cancers Therapeutics
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription issue that regulates the expression of goal genes upon binding to endogenous and exogenous elements. It performs a job in immune modulation and promotes tumor immune evasion by suppressing the exercise of various immune cells. AHR overexpression and constitutive activation have been noticed in numerous tumor varieties. Due to this fact, concentrating on AHR might present a brand new technique to stimulate anticancer immunity. The authors of this research reported the invention and preclinical characterization of IK-175, a potent and selective antagonist that binds to AHR with excessive affinity and disrupts AHR-dependent transcription in vitro. AHR inhibition with IK-175 shifted T cells from an immunosuppressive to a proinflammatory phenotype and modified the tumor immune microenvironment in tumor-bearing mice to a proinflammatory setting. IK-175 remedy inhibited tumor development each as a single agent and together with an immune checkpoint inhibitor. The antitumor exercise of IK-175 was additionally enhanced by mixture with the chemotherapy agent liposomal doxorubicin. The research confirmed that IK-175 had a good pharmacokinetic profile in preclinical fashions. In line with the authors, these findings present rationale for concentrating on AHR in sufferers, and IK-175 is being evaluated in a section I medical trial for superior strong tumors and urothelial carcinoma as a single agent and together with a checkpoint inhibitor. This text was highlighted within the August difficulty and featured on the cowl.
Journal: Medical Most cancers Analysis (August 15 difficulty)
First-In-Human Part I Examine of the OX40 Agonist MOXR0916 in Sufferers with Superior Stable Tumors
The OX40 receptor, which is transiently expressed on T cells upon antigen binding, performs co-stimulatory capabilities, mediating the survival and enlargement of each CD4+ and CD8+ effector cells. Agonist OX40 antibodies could promote antitumor immunity by stimulating effector T cells and inhibiting regulatory T cells. On this first-in-human research, the authors assessed the security, pharmacokinetics, and exercise of MOXR0916, a humanized agonist anti-OX40 monoclonal antibody, in sufferers with superior strong tumors together with melanoma, renal cell carcinoma, non–small cell lung carcinoma, urothelial carcinoma, and triple-negative breast most cancers. MOXR0916 was nicely tolerated, with sufferers experiencing gentle or reasonable hostile occasions together with fatigue, diarrhea, muscle ache, nausea, and decreased urge for food. Primarily based on the pharmacokinetic evaluation within the dose-expansion section of the research, the really helpful dose was 300 mg each three weeks. Total, 33 p.c of sufferers achieved secure illness, and one affected person with renal cell carcinoma and no prior checkpoint inhibitor remedy skilled a confirmed partial response. A subset of sufferers confirmed tumor immune activation. Though this research didn’t present a proof-of-concept for OX40 agonism efficacy, the authors counsel that it helps additional investigations together with different brokers with complementary mechanisms of motion. This research was highlighted within the August difficulty.
Journal: Most cancers Analysis (August 15 difficulty)
Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Most cancers
Molecular profiling of lung most cancers tissue is performed utilizing samples obtained via biopsy or surgical resection. Nevertheless, biopsy samples are tough to acquire and will comprise inadequate materials. Bronchoalveolar lavage (BAL) is an easy process that may very well be helpful for genomic profiling and prognosis however is presently not utilized for these functions. On this research, the authors explored the potential of performing cell-free DNA (cfDNA) evaluation on BAL samples to differentiate lung most cancers sufferers from risk-matched controls. They genotyped DNA extracted from BAL samples, plasma samples, and tumor samples from 38 sufferers with non–small cell lung most cancers (NSCLC) and 21 controls utilizing a way referred to as Most cancers Customized Profiling by Deep Sequencing (CAPP-Seq). This methodology allowed for the detection of lung tumor-derived mutations that have been enriched in BAL fluid in contrast with plasma. The researchers developed a BAL genomic classifier mannequin that displayed 69 p.c sensitivity and one hundred pc specificity in detecting lung most cancers and outperformed BAL cytology. In line with the authors, these outcomes warrant additional research to optimize the diagnostic purposes and medical utility of focused sequencing of BAL cfDNA. A commentary associated to this text is on the market right here.
Journal: Most cancers Analysis (August 1 difficulty)
The heterogeneity of driver mutations in a tumor can have vital implications for remedy and prognosis, however assessing heterogeneity requires genetic sequencing of a number of areas of the identical tumor. Whereas this strategy is restricted by technical and value concerns, a number of tumor sections are generally stained with hematoxylin and eosin (H&E) to visualise cell morphology. On this research, the researchers educated a synthetic intelligence (AI) mannequin to foretell which H&E-stained tumor sections had misplaced operate of the genes BAP1, PBRM1, and SETD2 in clear cell renal cell carcinoma (ccRCC). The coaching set consisted of 1,282 H&E-stained photos, in addition to details about expression of BAP1, PBRM1, and H3K36me3 (a readout of SETD2 exercise) from immunohistochemical stains of adjoining tumor areas. In a subset of 489 samples from the coaching set, a ccRCC cohort from The Most cancers Genome Atlas (TCGA), and two ccRCC tissue microarrays, the AI mannequin might successfully predict lack of every gene’s operate from an entire slide and from particular slide areas. BAP1 had the best prediction accuracy, with an space underneath the curve of 0.77, a sensitivity of 0.96, and a damaging predictive worth of 0.94. Utilizing medical knowledge from one of many tissue microarrays, the researchers discovered that people with decrease estimated BAP1 expression had an extended disease-specific survival than people with larger BAP1 expression, with a extra vital odds ratio than that calculated utilizing IHC alone. These knowledge counsel that morphological info could maintain vital insights into tumor heterogeneity, which can assist predict prognosis and decide remedy. A associated commentary is on the market right here.
Journal: Blood Most cancers Discovery
Views on the Threat-Stratified Therapy of A number of Myeloma
Therapy advances for sufferers with a number of myeloma have elevated survival charges; nonetheless, responses to remedy are heterogeneous. On this perspective piece, the authors summarize knowledge supporting a personalised, risk-stratified remedy strategy for a number of myeloma. They clarify that high-risk a number of myeloma is characterised by a excessive proliferation fee, resistance to apoptosis, focal and bone marrow-independent development, intraclonal heterogeneity, and numerous chromosomal translocations. The authors spotlight potential approaches to establish high-risk illness, together with gene expression profiling, entire genome or exome sequencing, and imaging. They advocate a number of adjustments to the administration of a number of myeloma, reminiscent of transitioning to next-generation sequencing-based diagnostic panels to establish high-risk illness, reimbursing the prices of such diagnostic exams, optimizing remedy primarily based on the affected person’s danger standing and tumor’s genetic options, striving for damaging minimal residual illness early within the remedy course, and larger enrollment into medical trials. In addition they present tips for designing risk-stratified medical trials.
Journal: Medical Most cancers Analysis (August 1 difficulty)
The chemotherapeutics eribulin and gemcitabine have every proven restricted efficacy in opposition to delicate tissue sarcomas in medical trials, and preclinical proof has instructed that they might have synergistic results when used collectively. On this section II medical trial, the researchers recruited 37 sufferers with liposarcoma or leiomyosarcoma, the 2 most typical delicate tissue sarcomas, whose tumors progressed following one or two doxorubicin-containing chemotherapy regimens, and handled the sufferers with eribulin plus gemcitabine. For sufferers with liposarcoma and leiomyosarcoma, respectively, the 12-week development free survival charges have been 75 p.c and 70.6 p.c, the general response charges have been 20 p.c and 11.8 p.c, and the illness management charges have been 80 p.c and 76.5 p.c. The researchers sequenced DNA and RNA from the tumors of 24 sufferers and located that elevated expression of genes within the TGFβ pathway correlated with decreased progression-free and general survival charges; nonetheless, this sample was not noticed in liposarcoma and leiomyosarcoma sufferers enrolled in The Most cancers Genome Atlas (TCGA), indicating that extra research are wanted to guage the affiliation between TGFβ and survival. These knowledge counsel that eribulin-gemcitabine mixture remedy ought to be studied in a bigger medical trial and could also be an efficient remedy for some sufferers with delicate tissue sarcomas. This research was highlighted within the August difficulty.
Journal: Most cancers Discovery
Stress Granules Decide the Improvement of Weight problems-Related Pancreatic Most cancers
Stress granules are non-membranous organelles that type in response to numerous stressors. In pancreatic most cancers, stress granules have been proven to reinforce resistance to chemotherapy and numerous stress stimuli. On this research, the authors investigated whether or not the formation of stress granules impacted pancreatic most cancers growth. They discovered that depletion of the G3BP1 protein in a pancreatic most cancers cell line impaired stress granule formation and tumor development when cells have been implanted into mice. The authors additionally discovered extra stress granules within the tumors of mice fed high-fat diets, in addition to in a genetic mouse mannequin of weight problems, suggesting a hyperlink between weight problems and stress granule formation. Inhibition of stress granule formation had a larger affect on tumor formation in overweight mice than in non-obese mice. Primarily based on these findings, the authors concluded that the event of obesity-associated pancreatic most cancers has a larger dependence on stress granules. Moreover, the authors recognized the serine-arginine protein kinase 2 (SRPK2) as a regulator of stress granule formation and confirmed that SRPK2-mediated stress granule formation is pushed by elevated activation of the insulin-responsive IGF1/PI3K/mTOR/S6K1 pathway, highlighting a possible therapeutic goal and offering mechanistic perception into the affiliation between weight problems and stress granule formation. This text is featured on the cowl and highlighted within the August difficulty.
Journal: Molecular Most cancers Analysis
The tumor suppressor p53 is mutated or silenced in as much as 60 p.c of strong tumors, and its repression in stromal fibroblasts has been proven to reinforce tumor growth. Nevertheless, little is thought about stromal p53 loss and its interactions with tumor oncogenes. On this research, the researchers designed mice with a p53 deletion in mammary stroma, alongside transgenic ERBB2 or KRASG12D expression in mammary epithelia. Stromal p53 deletion resulted in elevated tumor incidence and shorter time to tumor growth in KRASG12D mice however not in ERBB2 mice or mice with wild sort epithelia. In KRASG12D mice, stromal p53 deletion prompted elevated tumor and stromal cell proliferation, elevated DNA harm, and decreased apoptosis. Additional, stromal p53 deletion altered immune cell proportions in tumors, together with decreases in sure T-cell populations and will increase in myeloid-derived suppressor cells and macrophages. Previous to tumor growth, the mixture of stromal p53 deletion and epithelial KRASG12D mutation drove gene expression adjustments in each the stroma and epithelia. In two unbiased cohorts of affected person knowledge, stromal profiles correlated with decreased survival charges. These knowledge counsel that stromal p53 loss can have sturdy results on mammary epithelial tumor traits, and that these results can differ primarily based on oncogenic driver genes.
Journal: Most cancers Analysis Communications
Tumor Purity in Preclinical Mouse Tumor Fashions
Tumor purity is the proportion of most cancers cells current in a tumor tissue, which additionally incorporates non-cancerous cells, infiltrating immune cells, and blood vessels. Tumor purity in preclinical mouse fashions, that are broadly used to review tumor biology and analysis new most cancers therapies, could considerably affect outcomes. On this research, the authors performed a scientific evaluation of tumor purity in 27 patient-derived xenograft (PDX) fashions and 19 syngeneic tumor fashions utilizing next-generation sequencing knowledge from greater than 9,000 tumors. PDX fashions are established by serial transplantation of a affected person tumor fragment in immunodeficient mice. The authors discovered that the human stroma was quickly changed by mouse stroma after implantation. Tumor purity in these fashions was tumor-specific, with massive variations throughout completely different cancers; it mimicked the tumor purity of the unique affected person tumor, and barely elevated with passaging. Since completely different mouse strains have completely different immune infiltrate parts within the tumors, tumor purity was additionally pressure dependent. To estimate tumor purity in syngeneic tumors, the authors utilized a computational methodology leveraging the presence of unambiguously recognized somatic mutations. Just like what was noticed for PDX fashions, in syngeneic fashions, tumor purity was additionally an intrinsic property and was mannequin and most cancers particular. In line with the authors, this complete research will inform the usage of mouse fashions for tumor microenvironment analysis and anticancer drug growth.
Journal: Most cancers Prevention Analysis
Weight problems is related to an elevated danger of colorectal most cancers, and persistent irritation has been instructed as a part of the mechanism. The nonsteroidal anti-inflammatory drug (NSAID) sulindac has demonstrated antitumor exercise in each preclinical and medical research of colon most cancers, however its efficacy has not been evaluated within the context of weight problems. On this research, the authors fed mice a high-fat food plan (HFD) or low-fat food plan (LFD) containing the mutagenic agent azoxymethane to stimulate colon tumor growth. After 15 weeks, the HFD mice have been randomly assigned to stay on HFD or change to LFD, with or with out sulindac remedy. Seven weeks after the change, sulindac decreased tumor burden by 84 p.c in LFD mice, 86 p.c in HFD mice, and 78 p.c in mice that switched from HFD to LFD. Colon tumor samples from HFD mice confirmed upregulated expression of genes associated to cell migration, epithelial-to-mesenchymal transition, and immune suppression, and each sulindac and a change to LFD decreased expression of those genes. The researchers additionally recognized 13 taxa of fecal micro organism that considerably correlated with tumor multiplicity, seven of which have been modulated by sulindac in HFD mice and three of which have been modulated by sulindac and/or weight reduction in mice that switched from HFD to LFD. These knowledge display that each sulindac and weight reduction can modulate the gene expression and microenvironment of colorectal tumors, resulting in a lower in tumor burden. This research was featured on the cowl of the August difficulty.
