The lifestyle factors of physical activity, sedentary behaviour, and diet are increasingly being studied for their associations with cancer. Physical activity is inversely associated with and ...sedentary behaviour is positively (and independently) associated with an increased risk of more than ten types of cancer, including colorectal cancer (and advanced adenomas), endometrial cancers, and breast cancer. The most consistent dietary risk factor for premalignant and invasive breast cancer is alcohol, whether consumed during early or late adult life, even at low levels. Epidemiological studies show that the inclusion of wholegrain, fibre, fruits, and vegetables within diets are associated with reduced cancer risk, with diet during early life (age <8 years) having the strongest apparent association with cancer incidence. However, randomised controlled trials of diet-related factors have not yet shown any conclusive associations between diet and cancer incidence. Obesity is a key contributory factor associated with cancer risk and mortality, including in dose–response associations in endometrial and post-menopausal breast cancer, and in degree and duration of fatty liver disease-related hepatocellular carcinoma. Obesity produces an inflammatory state, characterised by macrophages clustered around enlarged hypertrophied, dead, and dying adipocytes, forming crown-like structures. Increased concentrations of aromatase and interleukin 6 in inflamed breast tissue and an increased number of macrophages, compared with healthy tissue, are also observed in women with normal body mass index, suggesting a metabolic obesity state. Emerging randomised controlled trials of physical activity and dietary factors and mechanistic studies of immunity, inflammation, extracellular matrix mechanics, epigenetic or transcriptional regulation, protein translation, circadian disruption, and interactions of the multibiome with lifestyle factors will be crucial to advance this field.
Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy Santarpia, Libero; Lippman, Scott M; El-Naggar, Adel K
Expert opinion on therapeutic targets,
2012-January, 1/1/2012, 2012-Jan, 2012-01-00, 20120101, Letnik:
16, Številka:
1
Journal Article
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Introduction:
The MAPK pathway comprises several key signaling components and phosphorylation events that play a role in tumorigenesis. These activated kinases transmit extracellular signals that ...regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK-ERK-MAPK (RAS-MAPK) pathway has been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. These pathways are considered potential therapeutic targets for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials.
Areas covered:
The biological role of the RAS-MAPK pathway, the consequence of its disregulation and the development of small-molecule inhibitors. The rationale for targeting the RAS-MAPK pathway and the application and the results of various inhibitory molecules as anticancer agents in clinical trials.
Expert opinion:
Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.
Advances in deep genomic sequencing have identified a spectrum of cancer-specific passenger and driver aberrations. Clones with driver anomalies are believed to be positively selected during ...carcinogenesis. Accumulating evidence, however, shows that genomic alterations, such as those inBRAF,RAS,EGFR,HER2,FGFR3,PIK3CA,TP53,CDKN2A, andNF1/2, all of which are considered hallmark drivers of specific cancers, can also be identified in benign and premalignant conditions, occasionally at frequencies higher than in their malignant counterparts. Targeting these genomic drivers can produce dramatic responses in advanced cancer, but the effects on their benign counterparts are less clear. This benign-malignant phenomenon is well illustrated in studies ofBRAFV600E mutations, which are paradoxically more frequent in benign nevi (∼80%) than in dysplastic nevi (∼60%) or melanoma (∼40%-45%). Similarly, human epidermal growth factor receptor 2 is more commonly overexpressed in ductal carcinoma in situ (∼27%-56%) when compared with invasive breast cancer (∼11%-20%).FGFR3mutations in bladder cancer also decrease with tumor grade (low-grade tumors, ∼61%; high-grade, ∼11%). "Driver" mutations also occur in nonmalignant settings:TP53mutations in synovial tissue from rheumatoid arthritis andFGFR3mutations in seborrheic keratosis. The latter observations suggest that the oncogenicity of these alterations may be tissue context-dependent. The conversion of benign conditions to premalignant disease may involve other genetic events and/or epigenetic reprogramming. Putative driver mutations can also be germline and associated with increased cancer risk (eg, germlineRASorTP53alterations), but germlineFGFR3orNF2abnormalities do not predispose to malignancy. We discuss the enigma of genetic "drivers" in benign and premalignant conditions and the implications for prevention strategies and theories of tumorigenesis.
Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed the outcomes of some malignancies
. Tumor complexity and ...heterogeneity suggest that the 'precision medicine' paradigm of cancer therapy requires treatment to be personalized to the individual patient
. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies
. Several of these trials have been hindered by very low matching rates, often in the 5-10% range
, and low response rates. Low matching rates may be due to the use of limited gene panels, restrictive molecular matching algorithms, lack of drug availability, or the deterioration and death of end-stage patients before therapy can be implemented. We hypothesized that personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies. As a first test of this concept, we implemented a cross-institutional prospective study (I-PREDICT, NCT02534675 ) that used tumor DNA sequencing and timely recommendations for individualized treatment with combination therapies. We found that administration of customized multidrug regimens was feasible, with 49% of consented patients receiving personalized treatment. Targeting of a larger fraction of identified molecular alterations, yielding a higher 'matching score', was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, compared to targeting of fewer somatic alterations. Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents.
We leveraged two trials to test the hypothesis of an inflammation-prostate cancer link prospectively in men without indication for biopsy.
Prostate Cancer Prevention Trial (PCPT) participants who had ...an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as "baseline." Five men with PSA > 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race.
Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (
= 41) and 68.2% of controls (
= 85) had at least one baseline biopsy core (∼5 evaluated per man) with inflammation. The odds of prostate cancer (
= 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum <4+3 disease (
= 31 cases; vs. 0%, >0-<1.8% OR = 1.70, 1.8-<5.0% OR = 2.39, ≥5% OR = 3.31,
= 0.047). In men previously in the finasteride arm, prevalence of inflammation did not differ between cases (76.5%;
= 51) and controls (75.0%;
= 108).
Benign tissue inflammation was positively associated with prostate cancer.
This first prospective study of men without biopsy indication supports the hypothesis that inflammation influences prostate cancer development.
.
CONTEXT The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a ...statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer. OBJECTIVE To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS A total of 35 533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34 887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011. INTERVENTIONS Oral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years. MAIN OUTCOME MEASURES Prostate cancer incidence. RESULTS This report includes 54 464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio HR, 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. CONCLUSION Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00006392
JAK: Not Just Another Kinase Agashe, Ruchi P; Lippman, Scott M; Kurzrock, Razelle
Molecular cancer therapeutics,
12/2022, Letnik:
21, Številka:
12
Journal Article
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The JAK/STAT axis is implicated in cancer, inflammation, and immunity. Numerous cytokines/growth factors affect JAK/STAT signaling. JAKs (JAK1, JAK2, JAK3, and TYK2) noncovalently associate with ...cytokine receptors, mediate receptor tyrosine phosphorylation, and recruit ≥1 STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Tyrosine-phosphorylated STATs dimerize and are then transported into the nucleus to function as transcription factors. Signaling is attenuated by specific suppressor of cytokine signaling proteins, creating a negative feedback loop. Both germline mutations and polymorphisms of JAK family members correlate with specific diseases: Systemic lupus erythematosus (TYK2 polymorphisms); severe combined immunodeficiency (JAK3 mutations); pediatric acute lymphoblastic leukemia (TYK2 mutations); and hereditary thrombocytosis (JAK2 mutations). Somatic gain-of-function JAK mutations mainly occur in hematologic malignancies, with the activating JAK2 V617F being a myeloproliferative disorder hallmark; it is also seen in clonal hematopoiesis of indeterminate potential. Several T-cell malignancies, as well as B-cell acute lymphoblastic leukemia, and acute megakaryoblastic leukemia also harbor JAK family somatic alterations. On the other hand, JAK2 copy-number loss is associated with immune checkpoint inhibitor resistance. JAK inhibitors (jakinibs) have been deployed in many conditions with JAK activation; they are approved in myeloproliferative disorders, rheumatoid and psoriatic arthritis, atopic dermatitis, ulcerative colitis, graft-versus-host disease, alopecia areata, ankylosing spondylitis, and in patients hospitalized for COVID-19. Clinical trials are investigating jakinibs in multiple other autoimmune/inflammatory conditions. Furthermore, dermatologic and neurologic improvements have been observed in children with Aicardi-Goutieres syndrome (a genetic interferonopathy) treated with JAK inhibitors.
This randomized trial tested the idea that finasteride, which inhibits the production of androgens within the prostate, can prevent prostate cancer. The participants were to receive finasteride or a ...placebo daily for seven years. Prostate cancer was found in 18.4 percent of the men in the finasteride group and in 24.4 percent of those in the placebo group. Higher-grade cancers (Gleason score, 7, 8, 9, or 10) were more common in the finasteride group than in the placebo group. Sexual dysfunction was more common in the finasteride group, and urinary difficulties were more common in the placebo group.
A test of the idea that finasteride can prevent prostate cancer.
To date, the management of prostate cancer, the most common nondermatologic neoplasm in men in the United States, has focused on early diagnosis and treatment. Given that the development of prostate cancer is a long-term process involving multiple steps, however, prevention may be a more effective approach.
There is abundant evidence that androgens influence the development of prostate cancer.
1
–
3
The development of finasteride, an inhibitor of steroid 5α-reductase, the enzyme that converts testosterone to the more potent androgen dihydrotestosterone, created an opportunity to test the possibility that lowering the androgen levels in the prostate would reduce the risk of . . .
Programmed death receptor-1/ligand 1 (PD-1/L1) antibodies can induce durable remissions in malignancies. However, response rates are only approximately 10% to 20% in unselected patients versus ...approximately 50% in microsatellite instability-high (MSI-high) tumors, probably related to high tumor mutational burden (TMB). Pembrolizumab is approved for MSI-high or deficient mismatch repair tumors. However, outside of colorectal and endometrial carcinoma, only a small subset of tumors were MSI-high, making this treatment option unavailable to most patients. It is not known if MS-stable tumors with high TMB respond to PD-1/PD-L1 blockade. Next-generation sequencing (NGS) was performed on 60 patients (14 different histologies) treated with checkpoint blockade using the FoundationOne assay to determine TMB and MSI status. TMB was dichotomized into two groups: low-to-intermediate (0-19 mutations/mb) versus high (≥20 mutations/mb). Benefit rate (stable disease for ≥6 months and partial or complete response) was determined: 2,179 of 148,803 samples (1.5%) were MSI-high and 9,762 (6.6%) TMB-high (7,972, MS-stable/TMB-high). The majority (82.1%) of MSI-H tumors were TMB-high; however, only 18.3% of TMB-high tumors were MSI-H. Median progression-free survival for MS-stable/TMB-high versus MS-stable/TMB-low/TMB-intermediate tumors was 26.8 versus 4.3 months (
= 0.0173). Thus, our data demonstrate that MS-stable/TMB-high tumors are more common than MSI-high cancers and may benefit from immunotherapy.
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