Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor ...(PPAR)α deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARα would promote tumor growth. Surprisingly, the PPARα agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPARα-deficient tumors were still susceptible to fenofibrate, absence of PPARα in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPARα as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPARα agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPARα agonists in cancer treatment, alone and in combination with other therapies.
ABSTRACT
Colon cancer recurrence after therapy, such as 5‐fluorouracil (5‐FU), remains a challenge in the clinical setting. Chemotherapy reduces tumor burden by inducing cell death; however, the ...resulting dead tumor cells, or debris, may paradoxically stimulate angiogenesis, inflammation, and tumor growth. Here, we demonstrate that 5‐FU‐generated colon carcinoma debris stimulates the growth of a subthreshold inoculum of living tumor cells in subcutaneous and orthotopic models. Debris triggered the release of osteopontin (OPN) by tumor cells and host macrophages. Both coinjection of debris and systemic treatment with 5‐FU increased plasma OPN levels in tumor‐bearing mice. RNA expression levels of secreted phosphoprotein 1, the gene that encodes OPN, correlate with poor prognosis in patients with colorectal cancer and are elevated in chemotherapy‐treated patients who experience tumor recurrence vs. no recurrence. Pharmacologic and genetic ablation of OPN inhibited debris‐stimulated tumor growth. Systemic treatment with a combination of a neutralizing OPN antibody and 5‐FU dramatically inhibited tumor growth. These results demonstrate a novel mechanism of tumor progression mediated by OPN released in response to chemotherapy‐generated tumor cell debris. Neutralization of debris‐stimulated OPN represents a potential therapeutic strategy to overcome the inherent limitation of cytotoxic therapies as a result of the generation of cell debris.—Chang, J., Bhasin,S. S., Bielenberg,D. R., Sukhatme,V. P., Bhasin,M., Huang,S., Kieran,M. W., Panigrahy,D.Chemotherapy‐generated cell debris stimulates colon carcinoma tumor growth via osteopontin. FASEB J. 33,114–125 (2019). www.fasebj.org
Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric ...gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.
Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without ...progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation.
Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial.
No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial.
Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid.
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.
The transition from childhood to adulthood through adolescence has been clearly identified as a time of great physical, psychological, emotional, social, and sexual change. Clinical care is currently ...divided into adult or pediatric care; adolescent patients require specific expertise that most clinical practices do not have. When illness coincides with the adolescent transition, the health system is severely challenged. Health systems historically have varied widely in the age they choose for allocating an individual to the adult model of health care. Tumors of the CNS complicate the difficult adjustments required in adolescents and young adults by virtue of their morbidity, complex treatment, and prognosis. Some brain tumors are unique to children, some occur predominantly in adults, and others peak in adolescence. Delays in the diagnosis of brain tumors can occur at any age but are particularly common in adolescence because of difficulties of accessing health systems, the difficulties of discriminating pathologic from typical adolescent behavioral characteristics, and changing endocrine function. Coming to terms with the cancer diagnosis; coping personally, socially, and financially with cancer treatments; accepting the risk of a shortened life span; confronting acquired disability; and coping with complex rehabilitation and adjusted plans for life are challenges for which there are no established specialist health models. This article will discuss the changing brain tumor profile of children, adolescents, and adults, with a focus on our limited understanding of the adolescent/young adult transition period.
Abstract
Background
Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by ...anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors.
Methods
This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir.
Results
Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7–17) and Lansky/Karnofsky performance scores were 60–100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1–2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection.
Conclusions
GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation.
Clinical trial registry
ClinicalTrials.gov NCT00634231
Background
To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single‐agent everolimus in pediatric patients with radiographically progressive low‐grade glioma (LGG).
Methods
...Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48‐week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients.
Results
Twenty‐three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2‐6.7 years), the 2‐, 3‐, and 5‐year progression‐free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2‐, 3‐, and 5‐year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5‐15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho‐S6, 4E‐BP1, and modulation of c‐Myc expression.
Conclusion
Daily oral everolimus provides a well‐tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.
Craniopharyngiomas are neoplasms of the sellar/parasellar region that are classified into adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) subtypes. Surgical resection ...of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible to BRAF/MEK inhibitors, but effective targeted therapies are needed for ACP. We explored the feasibility of targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway in ACP and PCP.
We mapped and quantified PD-L1 and PD-1 expression in ACP and PCP resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. We used tissue-based cyclic immunofluorescence to map the spatial distribution of immune cells and characterize cell cycle and signaling pathways in ACP tumor cells which intrinsically express PD-1.
All ACP (15 ± 14% of cells, n = 23, average ± SD) and PCP (35 ± 22% of cells, n = 18) resections expressed PD-L1. In ACP, PD-L1 was predominantly expressed by tumor cells comprising the cyst lining. In PCP, PD-L1 was highly expressed by tumor cells surrounding the stromal fibrovascular cores. ACP also exhibited tumor cell-intrinsic PD-1 expression in whorled epithelial cells with nuclear-localized beta-catenin. These cells exhibited evidence of elevated mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling. Profiling of immune populations in ACP and PCP showed a modest density of CD8+ T cells.
ACP exhibit PD-L1 expression in the tumor cyst lining and intrinsic PD-1 expression in cells proposed to comprise an oncogenic stem-like population. In PCP, proliferative tumor cells express PD-L1 in a continuous band at the stromal-epithelial interface. Targeting PD-L1 and/or PD-1 in both subtypes of craniopharyngioma might therefore be an effective therapeutic strategy.
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