Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy ...of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT). This innate mechanism could have a dual role during embryonic growth and organ differentiation, and in cancer progression, cancer stem cell intravasation, and metastasis settlement. Many of the molecular pathways decisive in EMT progression have been already unraveled, but little is known about the causes behind the induction of this mechanism. EMT is one of the most distinctive and critical features of PC, occurring even in the very first stages of tumor development. This is known as pancreatic intraepithelial neoplasia (PanIN) and leads to early dissemination, drug resistance, and unfavorable prognosis and survival. The intention of this review is to shed new light on the critical role assumed by EMT during PC progression, with a particular focus on its role in PC resistance.
Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study ...evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements.
In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed.
Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% 95% CI 26·5–45·4) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 60% of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 12%), arthralgia (nine 6%), stomatitis (eight 5%), hyponatraemia (eight 5%), abdominal pain (seven 5%), and fatigue (seven 5%). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven 5%), pyrexia (seven 5%), cholangitis (five 3%), and pleural effusion (five 3%). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 42%); no deaths were deemed to be treatment related.
These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.
Incyte Corporation.
Pemigatinib, a selective FGFR1-3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase II study in patients with cholangiocarcinoma harboring
fusions/rearrangements, and has gained ...regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma and to uncover unique molecular features of patients harboring
rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with
. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable
alterations were also identified. Our study provides a framework for molecularly guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy. SIGNIFICANCE: We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with
fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials.
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The Epithelial to Mesenchymal Transition (EMT) type 3 is a reversible dynamic process recognized as a major determinant of the metastatic event, although many questions regarding its role throughout ...this process remain unanswered. The ability of cancer cells to migrate and colonize distant organs is a key aspect of tumor progression and evolution, requiring constant tumor cells and tumor microenvironment (TME) changes, as well as constant changes affecting the cross-talk between the two aforementioned compartments. Alterations affecting tumor cells, such as transcription factors, trans-membrane receptors, chromatin remodeling complexes and metabolic pathways, leading to the disappearance of the epithelial phenotype and concomitant gaining of the undifferentiated mesenchymal phenotype are undoubtedly major players of the EMT process. However, several lines of evidence point out toward a more critical role of TME composition in creating an "EMT-permissive state." The "EMT-permissive state" consists in changes affecting physical and biochemical properties (i.e., stiffness and/or hypoxia) as well as changes of the TME cellular component (i.e., immune-cell, blood vessel, lymphatic vessels, fibroblasts, and fat cells) that favor and induce the epithelial mesenchymal transition. In this mini review, we will discuss the role of the tumor microenvironment cellular component that are involved in supporting the EMT, with particular emphasis on the immune-inflammatory cells component.
Altered expression of secreted factors by tumor cells or cells of the tumor microenvironment is a key event in cancer development and progression. In the last decade, emerging evidences supported the ...autocrine and paracrine activity of the members of the Angiopoietin-like (ANGPTL) protein family in angiogenesis, inflammation and in the regulation of different steps of carcinogenesis and metastasis development. Thus, ANGPTL proteins become attractive either as prognostic or predictive biomarkers, or as novel target for cancer treatment. Here, we outline the current knowledge about the functions of the ANGPTL proteins in angiogenesis, cancer progression and metastasis. Moreover, we discuss the most recent evidences sustaining their role as prognostic or predictive biomarkers for cancer therapy. Although the role of ANGPTL proteins in cancer has not been fully elucidated, increasing evidence suggest their key effects in the proliferative and invasive properties of cancer cells. Moreover, given the common overexpression of ANGPTL proteins in several aggressive solid tumors, and their role in tumor cells and cells of the tumor microenvironment, the field of research about ANGPTL proteins network may highlight new potential targets for the development of future therapeutic strategies.
IMPORTANCE: Chemotherapy is the recommended induction strategy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. However, the associated results on an intention-to-treat ...basis are poorly understood. OBJECTIVE: To investigate pragmatically the treatment compliance, conversion to surgery, and survival outcomes of patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma undergoing primary chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: This prospective study took place in a national referral center for pancreatic diseases in Italy. Consecutive patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma were enrolled at the time of diagnosis (January 2013 through December 2015) and followed up to June 2018. EXPOSURES: The chemotherapy regimen, assigned based on multidisciplinary evaluation, was delivered either at a hub center or at spoke centers. By convention, primary chemotherapy was considered completed after 6 months. After restaging, surgical candidates were selected based on radiologic and biochemical response. All surgeries were carried out at the hub center. MAIN OUTCOMES AND MEASURES: Rates of receipt and completion of chemotherapy, rates of conversion to surgery, and disease-specific survival. RESULTS: Of 680 patients, 267 (39.3%) had borderline resectable and 413 (60.7%) had locally advanced pancreatic ductal adenocarcinoma. Overall, 66 patients (9.7%) were lost to follow-up. The rate of chemotherapy receipt was 92.9% (n = 570). The chemotherapeutic regimens most commonly used included FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) (260 45.6%) and gemcitabine plus nanoparticle albumin-bound–paclitaxel (123 21.6%). Nineteen patients (3.3%) receiving chemotherapy died within 6 months, mainly for disease progression. The treatment completion rate was 71.6% (408 of 570). The overall rate of resection was 15.1% (93 of 614) (borderline resectable, 60 of 249 24.1%; locally advanced, 33 of 365 9%; resection:exploration ratio, 63.3%). Independent predictors of resection were age, borderline resectable disease, chemotherapy completion, radiologic response, and biochemical response. The median survival for the whole cohort was 12.8 (95% CI, 11.7-13.9) months. Factors independently associated with survival were completion of chemotherapy, receipt of complementary radiation therapy, and resection. In patients who underwent resection, the median survival was 35.4 (95% CI, 27.0-43.7) months for initially borderline resectable and 41.8 (95% CI, 27.5-56.1) months for initially locally advanced disease. No pretreatment and posttreatment factors were associated with survival after pancreatectomy. CONCLUSIONS AND RELEVANCE: This pragmatic observational cohort study with an intention-to-treat design provides real-world evidence of outcomes associated with the most current primary chemotherapy regimens used for borderline resectable and locally advanced pancreatic ductal adenocarcinoma.
Angiogenesis is one of the hallmarks of cancer, and the inhibition of pro-angiogenic factors and or their receptors has become a primary strategy for cancer therapy. However, despite promising ...results in preclinical studies, the majority of patients either do not respond to these treatments or, after an initial period of response, they develop resistance to anti-angiogenic agents. Thus, the identification of a novel therapeutic target is urgently needed. Multiple mechanisms of resistance to anti-angiogenic therapy have been identified, including the upregulation of alternative angiogenic pathways and the recruitment of pro-angiogenic myeloid cells in the tumor microenvironment. Homeobox containing (HOX) genes are master regulators of embryonic development playing a pivotal role during both embryonic vasculogenesis and pathological angiogenesis in adults. The importance of HOX genes during cancer progression has been reported in many studies. In this review we will give a brief description of the HOX genes and their involvement in angiogenesis and cancer, with particular emphasis on HOXB9 as a possible novel target for anti-angiogenic therapy. HOXB9 upregulation has been reported in many types of cancers and it has been identified as a critical transcription factor involved in resistance to anti-angiogenic drugs.
Cellular drug resistance remains the main obstacle to the clinical efficacy of cancer chemotherapy. Alterations in key pathways regulating cell cycle checkpoints, apoptosis and Epithelial to ...Mesenchymal Transition (EMT), such as the Mitogen-activated protein kinase (MAPK) pathway, appear to be closely associated to cancer chemoresistance.
Transforming growth factor-β (TGF-β)- activated kinase 1 (TAK1, also known as MAP3K7) is a serine/threonine kinase in the mitogen-activated protein kinase (MAP3K) family. It represents the cellular hub to which IL1, TGF-β and Wnt signaling pathways converge. By regulating the phosphorylation status and activities of transcription factors including Activated Protein-1 (AP-1) and nuclear factor κ-B (NF-κB), TAK1 mediates inflammatory and pro-survival responses. The interest towards the therapeutic targeting of TAK1 is due to its identification as one of the main mediators of both chemoresistance and EMT in several types of tumors, and as the possible target for a subset of treatment-refractory colon cancers exhibiting mutated KRAS or activated WNT pathways. For these reasons, many efforts have been made to design inhibitors of TAK1 kinase activity, which could be used to reverse TAK1-mediated chemoresistance. The activity of these inhibitors, in combination with the most commonly used chemotherapeutic drugs, has been tested in preclinical studies, proving the efficacy of TAK1 inhibition in reducing tumor growth and survival following chemotherapy administration. In the first part of this review, we describe the mechanisms underlying TAK1 regulation such as phosphorylation, ubiquitination and targeting by microRNAs. We then focus on the development of therapeutic small molecule inhibitors of TAK1 kinase activity, as well as preclinical studies supporting the role of TAK1 as a potential target for enhancing the response of tumors to anticancer therapies.
The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor ...resistance to the anti-VEGF agent bevacizumab.
HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoietin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, IL8, and TGFβ1 in tumor-bearing mice were measured by multiplex xMAP technology. HOXB9 expression was measured by immunohistochemical analysis in 81 pretreatment specimens from metastatic colorectal cancer patients. Differences in progression-free survival (PFS) were determined using a log-rank test.
HOXB9-positive tumors were resistant to bevacizumab, whereas mice bearing HOXB9-negative tumors were cured by this agent. Silencing HOXB9 in bevacizumab-resistant models significantly (
< 0.05) reduced Angptl2, CXCL1, IL8, and TGFβ1 levels, reverted their mesenchymal phenotype, reduced CD11b+ cells infiltration, and restored, in turn, sensitivity to bevacizumab. HOXB9 had no prognostic value in patients treated with a first-line chemotherapeutic regimen noncontaining bevacizumab. However, patients affected by an HOXB9-negative tumor had a significantly longer PFS compared with those with an HOXB9-positive tumor if treated with a first-line regimen containing bevacizumab (18.0 months vs. 10.4 months; HR 2.037; 95% confidence interval, 1.006-4.125;
= 0.048).
These findings integrate the complexity of numerous mechanisms of anti-VEGF resistance into the single transcription factor HOXB9. Silencing HOXB9 could be a promising approach to modulate this resistance. Our results candidate HOXB9 as predictive biomarker for selecting colorectal cancer patients for antiangiogenic therapy.
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Background
Nutritional derangements are common hallmarks of pancreatic cancer (PC). Their early detection and management are usually overlooked in routine practice. This study aimed to explore ...preoperative nutritional status and its prognostic value in patients undergoing surgery for PC.
Methods
Data from 73 patients who underwent surgery for PC from November 2015 to January 2018 at the General and Pancreatic Surgery Unit, The Pancreas Institute, University Hospital of Verona Hospital, Verona, Italy, were retrospectively evaluated. The Nutritional Risk Screening (NRS)-2002 was used to evaluate the preoperative nutritional risk. Body composition was assessed using bioimpedance vectorial analysis (BIVA) on the day prior to surgery. The effect of clinical, pathological, and nutritional characteristics on overall survival (OS) was investigated using a Cox and logistic regression model. Kaplan–Meier curves were compared using the log-rank test.
Results
Most patients (80.8%) were at preoperative risk of malnutrition (NRS-2002 ≥ 3) despite a mean BMI of 24.1 kg/m
2
(± 4.3). Twenty-four patients (32.9%) received neoadjuvant therapy prior to surgery. Preoperative NRS-2002 was significantly higher in this subset of patients (
p
= 0.026), with a significant difference by chemotherapy regimens (in favor of FOLFIRINOX,
p
= 0.035). In a multivariate analysis, the only independent prognostic factor for OS was the NRS-2002 score (HR 5.24,
p
= 0.013). Particularly, the likelihood of 2-year survival was higher in NRS < 3 (
p
= 0.009).
Conclusions
Our analysis confirms that preoperative malnutrition has a detrimental impact on OS in PC patients undergoing radical surgery for PC. Careful preoperative nutritional evaluation of PC patients should be mandatory, especially in those who are candidates for neoadjuvant therapy.
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