Abstract The advent of the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs), cetuximab and panitumumab has expanded the range of treatment options for metastatic ...colorectal cancer (CRC). Despite these agents have paved the way to individualized therapy, our understanding why some patients respond to treatment whereas others do not remain poor. The realization that detection of positive EGFR expression by IHC does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of benefit to anti-EGFR mAbs. Oncologists are now facing emerging issues in the treatment of metastatic CRC, including the identification of additional genetic determinants of primary resistance to EGFR-targeted therapy for further improving selection of patients, the explanation of rare cases of patients carrying KRAS-mutated tumours who have been reported to respond to cetuximab and panitumumab and the discovery of mechanisms of secondary resistance to EGFR-targeted therapy. Current data suggest that, together with KRAS mutations, the evaluation of EGFR gene copy number (GCN), BRAF, NRAS, PIK3CA mutations or loss of PTEN expression could also be useful for selecting patients with reduced chance to benefit from anti-EGFR mAbs. This review aims to provide an updated of the most recent data on predictive and prognostic biomarkers within the EGFR pathway, the challenges this emerging field presents and the future role of these molecular markers in CRC treatment.
Hypomethylation of LINE-1 elements has emerged as a distinguishing feature in human cancers. Limited evidence indicates that some LINE-1 elements encode an additional internal antisense promoter, and ...increased hypomethylation of this region may lead to inadvertent activation of evolutionarily methylation-silenced downstream genes. However, the significance of this fundamental epigenetic mechanism in colorectal cancer (CRC) has not been investigated previously.
We analysed tissue specimens from 77 CRC patients with matched sets of normal colonic mucosa, primary CRC tissues (PC), and liver metastasis tissues (LM). LINE-1 methylation levels were determined by quantitative bisulfite pyrosequencing. MET, RAB3IP and CHRM3 protein expression was determined by western blotting and IHC. MET proto-oncogene transcription and 5-hydroxymethylcytosine (5-hmc) were evaluated by quantitative real-time-PCR.
Global LINE-1 methylation levels in LM were significantly lower compared with the matched PC (PC=66.2% vs LM=63.8%; p<0.001). More importantly, we observed that specific LINE-1 sequences residing within the intronic regions of multiple proto-oncogenes, MET (p<0.001), RAB3IP (p=0.05) and CHRM3 (p=0.01), were significantly hypomethylated in LM tissues compared with corresponding matched PC. Furthermore, reduced methylation of specific LINE-1 elements within the MET gene inversely correlated with induction of MET expression in CRC metastases (R=-0.44; p<0.0001). Finally, increased 5-hmc content was associated with LINE-1 hypomethylation.
Our results provide novel evidence that hypomethylation of specific LINE-1 elements permits inadvertent activation of methylation-silenced MET, RAB3IP and CHRM3 proto-oncogenes in CRC metastasis. Moreover, since 5-hmc content inversely correlated with LINE-1 hypomethylation in neoplastic tissues, our results provide important mechanistic insights into the fundamental processes underlying global DNA hypomethylation in human CRC.
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the ...development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC.
At the time of diagnosis, 20% of patients with colorectal cancer present metastasis. Among individuals with primary lesions, 50% of them will develop distant tumours with time. Therefore, early ...diagnosis and prediction of aggressiveness is crucial for therapy design and disease prognosis. Tumoral cells must undergo significant changes in energy metabolism to meet increased structural and energetic demands for cell proliferation, and metabolic alterations are considered to be a hallmark of cancer. Here, we present the ATP‐binding cassette transporter (ABCA1), a regulator of cholesterol transport, as a new marker for invasion and colorectal cancer survival. ABCA1 is significantly overexpressed in patients at advanced stages of colorectal cancer, and its overexpression confers proliferative advantages together with caveolin‐1 dependent‐increased migratory and invasive capacities. Thus, intracellular cholesterol imbalances mediated by ABCA1 overexpression may contribute to primary tumour growth and dissemination to distant locations. Furthermore, we demonstrate here that increased levels of apolipoprotein A1 (APOA1), a protein involved in cholesterol efflux and high‐density lipoprotein constitution, in the extracellular compartment modulates expression of ABCA1 by regulating COX‐2, and compensate for ABCA1‐dependent excessive export of cholesterol. APOA1 emerges as a new therapeutic option to inhibit the promotion of colorectal cancer to metastasis by modulating intracellular cholesterol metabolism. Furthermore, we propose apabetalone, an orally available small molecule that is currently being evaluated in clinical trials for the treatment of atherosclerosis, as a new putative therapeutic option to prevent colorectal cancer progression by increasing APOA1 expression and regulating reverse transport of cholesterol.
ABCA1 overexpression leads to increased proliferation, epithelial‐to‐mesenchymal transition and promotes migration and invasion by regulating Caveolin‐1 stability. In each of these steps of tumorigenesis, apabetalone can regulate the expression of the cholesterol transporter, thereby acting as a bona fide inhibitor of colorectal cancer invasiveness.
Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining ...immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC.
Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with
metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability.
A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.
Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.
Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. ...Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma.
Highlights • The comprehensive study of molecular changes in colorectal cancer identifies potential therapeutic targets. • The integrative analysis of distinct molecular sybtypes can led to ...individualized approach to therapeutics. • The predictive and prognostic approach is useful in adjuvant setting and also in treatment selection in metastasic disease in CRC patients.
Current systemic therapies for metastatic pancreatic ductal adenocarcinoma are associated with poor outcomes with a 5-year overall survival rate under 5%. We aimed to assess the safety and antitumour ...activity of mitazalimab, a human CD40 agonistic IgG1 antibody, with modified FOLFIRINOX (mFOLFIRINOX; fluorouracil, leucovorin, oxaliplatin, and irinotecan), in chemotherapy-naive patients with metastatic pancreatic ductal adenocarcinoma.
OPTIMIZE-1 was a single-arm, multicentre, phase 1b/2 study which enrolled adults with histologically-confirmed metastatic pancreatic ductal adenocarcinoma and European Cooperative Oncology Group performance status 0 or 1 in 14 university hospitals in Belgium, France, and Spain. The primary endpoint of phase 1b was to determine the recommended phase 2 dose of intravenous mitazalimab (450 μg/kg or 900 μg/kg) when combined with intravenous mFOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, fluorouracil 2400 mg/m2). In the first 21-day treatment cycle, mitazalimab was administered on days 1 and 10, and mFOLFIRINOX on day 8. In subsequent 14-day cycles mitazalimab was administered 2 days after mFOLFIRINOX. The phase 2 primary endpoint was objective response rate. Activity and safety analyses were conducted on the full analysis set (all patients who received the combination of mitazalimab at the recommended phase 2 dose and mFOLFIRINOX for at least two treatment cycles) and safety set (all patients who received any study treatment), respectively. Enrolment is complete, and data represents a primary analysis of the ongoing trial. The trial is registered at Clinicaltrials.gov (NCT04888312).
Between Sept 29, 2021, and March 28, 2023, 88 patients were screened and 70 patients were enrolled (40 57% were female and 30 43% were male). In phase 1b, 900 μg/kg mitazalimab was determined as the recommended phase 2 dose. Overall, five patients received 450 μg/kg mitazalimab; 65 received 900 μg/kg mitazalimab. No dose-limiting toxicities were observed at 450 μg/kg, and one dose-limiting toxicity was observed at 900 μg/kg. 57 patients were evaluated for activity, and all 70 patients were included in the safety set. At data cutoff on Nov 14, 2023, median follow-up was 12·7 months (95% CI 11·1–15·7). Of the 57 patients, 29 (51%) remained on study and 18 (32%) remained on treatment. The primary endpoint (objective response rate >30%) was met (objective response rates in 23 40%; one-sided 90% CI ≥32 of 57 patients). The most common grade 3 or worse adverse events were neutropenia (18 26% of 70 patients), hypokalaemia (11 patients 16%), and anaemia and thrombocytopenia (eight patients 11%). Serious adverse events were reported in 29 (41%) of 70 patients, the most common being vomiting (five 7% of 70 patients), decreased appetite (four 6%), and diarrhoea and cholangitis (three 4% of 70 patients for each), none considered related to mitazalimab. No treatment-related deaths were reported.
Mitazalimab with mFOLFIRINOX demonstrated manageable safety and encouraging activity, warranting continued development in a phase 3, randomised, controlled trial. The results from OPTIMIZE-1 pave the way for further exploration and confirmation of a novel immunotherapy treatment regimen for metastatic pancreatic ductal adenocarcinoma, which is a complex and aggressive cancer with very low survival rates and restricted treatment options.
Alligator Bioscience.
Osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), undergoes significant hepatic elimination. In this phase 1 study, we assessed the effects of mild and moderate ...hepatic impairment on the pharmacokinetics (PK) of osimertinib in patients with malignant solid tumors. In part A, patients with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, according to the Child-Pugh classification, received a single 80 mg oral dose of osimertinib. Standard PK measures were assessed. In part B, patients could continue osimertinib treatment if deemed clinically appropriate. We compared these study results with a population PK analysis including other osimertinib clinical studies. Geometric mean osimertinib plasma concentrations were lower in patients with mild (
= 7) or moderate hepatic impairment (
= 5) versus normal hepatic function (
= 10):
was reduced to 51% and 61%, respectively; area under the curve was reduced to 63% and 68%, respectively. PK results for the metabolites were similar. No apparent differences in the safety profile were found between patients with normal hepatic function and patients with mild or moderate hepatic impairment. Comparison of these study results with National Cancer Institute-Organ Dysfunction Working Group criteria from population PK analysis showed osimertinib exposure was not affected by hepatic impairment. No dose adjustment is required for osimertinib when treating patients with mild or moderate hepatic impairment. No apparent differences in the safety of osimertinib were found between patients with normal hepatic function and mild or moderate hepatic impairment.
Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. ...Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving.
We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation.
Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R.
Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.
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