Resistance of pancreatic ductal adenocarcinoma (PDAC) to radiotherapy and chemotherapy represents a significant clinical issue. Although the mechanisms of resistance are multi‐faceted, client ...proteins of heat shock protein 90 (HSP90) such as hypoxia induced factor‐1α (HIF‐1α) have a central role in this process. The purpose of this investigation was to evaluate inhibition of HSP90 as a therapeutic strategy for radiosensitization in pancreatic cancer. Ganetespib, a selective inhibitor of HSP90, was evaluated as a radio‐sensitizer in setting of PDAC. Inhibition of HSP90 by ganetespib potentiated the ability of radiation therapy to limit cell proliferation and colony formation in vitro. HIF‐1α expression was upregulated by irradiation and HIF‐1α‐overexpressing stable cell lines were resistant to radiation. Inhibition of HSP90 with ganetespib reversed the effects of HIF‐1α overexpression, by reducing signaling via proliferative, angiogenic and anti‐apoptotic pathways. The potentiation of the antitumor effects of chemoradiotherapy by ganetespib and modulation of key pathways (e.g. HIF‐1α, STAT3, and AKT) was confirmed in vivo in nude mice bearing HPAC xenograft tumors. These novel data highlight HIF‐1α‐mediated mechanisms of HSP90 inhibition that sensitize PDAC cells to chemoradiotherapy. This pathway and its pleiotropic effects warrant further evaluation in concert with conventional therapy in pancreatic cancer clinical trials.
What's new?
A major challenge in pancreatic cancer is primary resistance to chemoradiotherapy. Although the mechanisms of resistance are multi‐faceted, client proteins of heat shock protein 90 (HSP90) such as hypoxia induced factor‐1 α (HIF‐1α) play a central role. Here, the authors show that the HSP90 inhibitor ganetespib can down‐regulate HIF‐1α pathways in addition to survival and angiogenic pathways in pancreatic cancer cell lines resistant to chemoradiotherapy, resulting in their resensitization to treatment. These findings are important for elucidating mechanisms of resistance in pancreatic cancer and for developing clinically‐relevant strategies such as combination treatments to overcome chemoradioresistance.
Summary Background 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and ...fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population. Methods We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan–Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model. Findings We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0–16·0) to 32·7 months (23·1–42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7–26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5–34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8–16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3–81·6, I2 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2–31·9, I2 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2–92·2, I2 64%). Interpretation Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months—longer than that reported with gemcitabine (6–13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX. Funding None.
Cyclooxygenase (COX) is an enzyme complex that plays an important role in the conversion of arachidonic acid to prostaglandins. Prostaglandins are essential modulators of signal transduction ...pathways, which contribute to the metastatic properties of gastrointestinal (GI) malignancies. Although COX‐1 is constitutively active, COX‐2 is upregulated by cytokines, growth factors, and mitogen. COX‐2 is involved in malignant cell proliferation, angiogenesis, migration, invasion, and antiapoptotic activity. Thus, COX‐2 inhibitors may represent a promising therapeutic strategy for the treatment of GI cancers. In this review, the role of COX‐2 in GI cancers is explored, and its clinical applications as a therapeutic target are discussed.
The role of cyclooxygenase‐2 in the development of gastrointestinal malignancies is described, and the authors explore how cyclooxygenase‐2 could represent a novel therapeutic target in gastrointestinal cancers.
Epigenetics in hepatocellular carcinoma Nagaraju, Ganji Purnachandra; Dariya, Begum; Kasa, Prameswari ...
Seminars in cancer biology,
11/2022, Letnik:
86, Številka:
Pt 3
Journal Article
Recenzirano
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and has a high fatality rate. Genetic and epigenetic aberrations are commonly observed in HCC. The epigenetic ...processes include chromatin remodelling, histone alterations, DNA methylation, and noncoding RNA (ncRNA) expression and are connected with the progression and metastasis of HCC. Due to their potential reversibility, these epigenetic alterations are widely targeted for the development of biomarkers. In-depth understanding of the epigenetics of HCC is critical for developing rational clinical strategies that can provide a meaningful improvement in overall survival and prediction of therapeutic outcomes. In this article, we have summarised the epigenetic modifications involved in HCC progression and highlighted the potential biomarkers for diagnosis and drug development.
Objective
Appendiceal mucinous neoplasms (AMNs) are a rare and heterogeneous disease for which clinical management is challenging. We aim to review the literature regarding modalities of treatment to ...guide the management of AMNs.
Methods and Review Criteria
We conducted a PubMed search in February 2016 for English‐language publications, using the terms “appendiceal,” “appendix,” “carcinoma,” “cancer,” “mucinous,” “treatment,” “genes,” “target,” “genomic,” and terms listed in the articles' subheadings. Published reports and s from the American Society of Clinical Oncology meetings were also searched.
Results
In this review, we summarize current data and controversies in AMN classification, clinical presentation, molecular alterations, treatment outcomes with regard to cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and the role of systemic chemotherapy.
Conclusion
Appendiceal mucinous neoplasms are a heterogeneous group of tumors with a rising incidence. Treatment is based on stage and histology. Low‐grade tumors are treated surgically with resection of the primary site in early stage disease, or peritoneal debulking and HIPEC in patients with advanced stage disease. Treatment of high‐grade tumors requires further prospective trials, and options include debulking surgery and HIPEC with or without preoperative chemotherapy. Trials evaluating novel therapies based on the molecular profiling of AMN tumors are needed to evaluate therapeutic options in patients who are not surgical candidates.
Implications for Practice
This review provides a reference to guide gastroenterologists, pathologists, surgeons, and oncologists in the management of appendiceal mucinous neoplasms (AMNs), a rare and heterogeneous disease with no consensus on histologic classification or guidelines for treatment algorithms. This review summarizes all AMN classifications and proposes a treatment algorithm based on stage and histology of disease.
Appendiceal mucinous neoplasms are rare and challenging to manage. This review summarizes the current literature and controversies in classification, clinical presentation, molecular alterations, and treatment outcomes in this heterogeneous group of tumors and provides guidelines for treatment.
Communication between the cell and its surrounding environment, consisting of proteinaceous (non-living material) and extracellular matrix (ECM), is important for bio-physiological and chemical ...signaling. This signaling results in a range of cellular activities, including cell division, adhesion, differentiation, invasion, migration, and angiogenesis. The ECM non-structural secretory glycoprotein called “secreted protein, acidic and rich in cysteine (SPARC), plays a significant role in altering cancer cell activity and the tumor's microenvironment (TME). However, the role of SPARC in cancer research has been the subject of controversy. This review mainly focuses on recent advances in understanding the contradictory nature of SPARC in relation to ECM assembly, cancer cell proliferation, adhesion, migration, apoptosis and tumor growth.
Background
Optimal prognostic and predictive biomarkers for patients with advanced‐stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the ...neutrophil‐to‐lymphocyte ratio (NLR), the monocyte‐to‐lymphocyte ratio (MLR), and the platelet‐to‐lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced‐stage cancer who received IO.
Methods
A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO‐based treatment regimens. NLR, MLR, and PLR values were log‐transformed and treated as continuous variables for each patient. Overall survival (OS), progression‐free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional‐hazards models or logistic regression models were used.
Results
The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052).
Conclusions
Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO‐based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late‐stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents.
High baseline and early increases in the neutrophil‐to‐lymphocyte, monocyte‐to‐lymphocyte, and platelet‐to‐lymphocyte ratios are significantly associated with poor outcomes in patients with advanced‐stage cancer who receive immunotherapy. These markers of inflammation may warrant consideration in updated prognostic models for patients enrolled on phase 1 clinical trials.
Curcumin is a polyphenolic constituent of turmeric that is known to have various molecular effects in preclinical models, leading to prevention and anticancer properties. In clinical trials, curcumin ...has failed to demonstrate activity against pancreatic cancer possibly due to its low bioavailability and potency. Using the curcumin molecular model, our group and others have synthesized several analogs with better bioavailability and higher potency in pancreatic cancer in vitro and xenograft models. This mini review summarizes some of the known molecular effects of curcumin analogs and their potential role as novel therapeutics for pancreatic cancer.
Background
The induction of reactive oxygen species (ROS) represents a viable strategy for enhancing the activity of radiotherapy. The authors hypothesized that napabucasin would increase ROS via its ...ability to inhibit NAD(P)H:quinone oxidoreductase 1 and potentiate the response to chemoradiotherapy in rectal cancer via distinct mechanisms.
Method
Proliferation studies, colony formation assays, and ROS levels were measured in HCT116 and HT29 cell lines treated with napabucasin, chemoradiation, or their combination. DNA damage (pγH2AX), activation of STAT, and downstream angiogenesis were evaluated in both untreated and treated cell lines. Finally, the effects of napabucasin, chemoradiotherapy, and their combination were assessed in vivo with subcutaneous mouse xenograft models.
Results
Napabucasin significantly potentiated the growth inhibition of chemoradiation in both cell lines. Napabucasin increased ROS generation. Inhibition of ROS by N‐acetylcysteine decreased the growth inhibitory effect of napabucasin alone and in combination with chemoradiotherapy. Napabucasin significantly increased pγH2AX in comparison with chemoradiotherapy alone. Napabucasin reduced the levels of pSTAT3 and VEGF and inhibited angiogenesis through an ROS‐mediated effect. Napabucasin significantly potentiated the inhibition of growth and blood vessel formation by chemoradiotherapy in mouse xenografts.
Conclusion
Napabucasin is a radiosensitizer with a novel mechanism of action: increasing ROS production and inhibiting angiogenesis. Clinical trials testing the addition of napabucasin to chemoradiotherapy in rectal cancer are needed.
Napabucasin increases reactive oxygen species production through NAD(P)H:quinone oxidoreductase 1 modulation in rectal cancer cells and mouse xenografts. The addition of napabucasin to chemoradiotherapy can elicit DNA damage and inhibit rectal cancer growth and survival.
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