Therapy For Advanced Colorectal Cancer Research Articles

Antimigratory Effect of Lipophilic Cations Derived from Gallic and Gentisic Acid and Synergistic Effect with 5-Fluorouracil on Metastatic Colorectal Cancer Cells: A New Synthesis Route.

Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC-such as 5-fluorouracil (5FU)-remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.

Ramucirumab in second‑line advanced colorectal cancer therapy: A study on therapeutic outcomes and hepatic sinusoidal platelet aggregation.

The present study investigated the role of ramucirumab (RAM) in treating liver metastases (LMs) as a second-line or salvage treatment in patients with advanced CRC. Of the 36 patients, 21 (58%) received RAM plus folinic acid, fluorouracil and irinotecan (FOLFIRI) as second-line treatment, whereas 15 (42%) received it in a salvage setting. The median overall survival time was 23 months [95% confidence interval (CI), 12-34 months] for those in the second-line treatment group and 8 months (95% CI, 5-19 months) for those in the salvage treatment group. Of the 36 patients, 14 (39%) underwent surgical resection of LMs during chemotherapy. A total of 6 patients underwent surgical resection for LMs for the first time during second-line RAM plus FOLFIRI (RAM-LM); of the remaining 8 patients, 6 underwent resection of LMs during first-line bevacizumab (BEV)-based chemotherapy (BEV-LM). Immunohistochemical analysis of CD42b showed that the platelet aggregation score (CD42b score), which ranges from 0 (absence of deposition) to 3 (presence of linear deposition), tended to decrease with the increasing duration of treatment with both RAM and BEV. Although there was no significant difference in the mean duration of anti-VEGF antibody treatment between the BEV-LM and RAM-LM groups, the median CD42b score was higher in the RAM-LM group (median CD42b score, 3; range, 0-3) compared with that in the BEV-LM group (median CD42b score, 1; range, 0-3; P=0.01), suggesting that RAM induces a different degree of platelet aggregation in liver sinusoids compared to BEV.

Olaparib with or without bevacizumab versus bevacizumab plus a fluoropyrimidine as maintenance therapy in advanced colorectal cancer: The randomized phase 3 LYNK-003 study

BackgroundThe randomized, open-label, phase III LYNK-003 study assessed the efficacy of first-line maintenance olaparib, alone or in combination with bevacizumab, versus bevacizumab plus a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer (mCRC). We present results of the prespecified interim futility analysis. MethodsEligible participants were ≥18 years of age with unresectable or mCRC that had not progressed after induction with first-line bevacizumab plus 5-fluorouracil plus oxaliplatin plus leucovorin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX). Participants were randomly assigned 1:1:1 to olaparib plus bevacizumab, olaparib alone, or bevacizumab plus a fluoropyrimidine (5-fluorouracil or capecitabine). The primary end point was progression-free survival (PFS) per RECIST v1.1 by central review. ResultsBetween August 2020 and May 2022, 309 participants were assigned to olaparib plus bevacizumab (n = 104), olaparib (n = 107), or bevacizumab plus fluoropyrimidine (n = 98). At interim analysis, with a median follow-up of 7.6 months (range 0.1–19.7 months), the median PFS was 3.7 months (95% CI 2.8–5.3) with olaparib plus bevacizumab (HR 1.52; 95% CI 1.02–2.27; P = 0.982) and 3.5 months (95% CI 2.0–3.7) with olaparib (HR 2.11; 95% CI 1.39–3.18; P = 0.999) versus 5.6 months (95% CI 3.8–5.9) with bevacizumab plus fluoropyrimidine. Treatment-related adverse events occurred in 64 (62%), 52 (50%), and 57 (59%) participants, respectively. There were no treatment-related deaths. ConclusionThe LYNK-003 study was stopped prematurely as criteria for futility were met. Maintenance olaparib with or without bevacizumab did not demonstrate clinical efficacy compared with bevacizumab plus a fluoropyrimidine. ClinicalTrials.gov registrationNCT04456699

Anti-PD-1 therapy for advanced colorectal cancer based on intestinal microecology.

To explore the effects of anti-programmed death-1 (PD-1) therapy on advanced colorectal cancer (CRC) based on the intestinal microecology.Ninety-two patients with advanced CRC were selected. Patients were treated with Apatinib alone or anti PD-1 treatment combined with Apatinib. The lactulose/mannitol (L/M) value of the urine was detected by high performance liquid chromatography. The changes of intestinal microflora were determined by real-time fluorescence quantitative PCR. The risk factors were analyzed through multivariate logistic regression analysis.The curative effect of anti PD-1 treatment combined with the Apatinib treatment (82.61%) was much higher than that of the Apatinib treatment alone (63.04%, p < 0.05). After treatment, the contents of Bifidobacterium, Lactobacillus, and Enterococcus faecalis were higher with lower levels of Escherichia coli in the observation group than the control (p < 0.05). The level of D-lactic acid and urinary L/M value of the urine in the observation group was lower than that in control after treatment (p < 0.001). The patients had a 3-year survival rate of 91.30%. Age >60 years old, histological types of mucinous adenocarcinoma and signet ring cell carcinoma, vascular tumor thrombus, nerve invasion, TNM stage of Ⅲ-Ⅳ were independent risk factors, and anti PD-1 treatment was the protective factor (p < 0.05).In advanced CRCpatients receivinganti PD-1 treatment combined with the Apatinib treatment, the progression of advanced CRC was effectively controlled by maintaining the intestinal microflora balance. Anti PD-1 therapy can improve the living quality of CRC patients.

Immune checkpoint inhibition in advanced colorectal cancer with inherited and acquired microsatellite instability: Current state and future directions.

This paper reviews comprehensively the most relevant data on single-agent and combination therapies for advanced colorectal cancer with inherited and acquired microsatellite instability (MSI). We performed a systematic search on PubMed and MEDLINE articles published from inception to December 2022. We have also searched independent websites including U.S. Food and Drug Administration and ClinicalTrials.gov. Performing microsatellite stability testing, tumor mutational burden (TMB), and germline mutation analysis could identify patients with metastatic colorectal cancer that benefit from immune checkpoint inhibitor (ICI) therapy. Single-agent pembrolizumab has proven superiority over traditional chemotherapy in these patients. The nivolumab-ipilimumab is the only combination ICI therapy approved in this space. Recently, the anti-PD-1 antibody dostarlimab was granted Food and Drug Administration approval in refractory tissue-agnostic advanced solid cancers with deficient mismatch repair (dMMR). ICIs are also being studied in the adjuvant/neoadjuvant setting in colon cancer patients with dMMR. Newer agents are being scrutinized in this space as well. More solid data on biomarkers predicting responses in patients with MSI-high or TMB-H to various therapies are needed. Given its both clinical and financial toxicity, it is imperative to determine the optimal duration of ICI therapy in individual patients. Overall, the outlook in advanced colorectal cancer patients with MSI appears optimistic as new and efficacious ICI drugs and combinations are being added to the existing therapeutic armamentarium.

XPF-ERCC1 Blocker Improves the Therapeutic Efficacy of 5-FU- and Oxaliplatin-Based Chemoradiotherapy in Colorectal Cancer.

5-FU-based chemoradiotherapy (CRT) and oxaliplatin-based CRT are commonly used therapies for advanced colorectal cancer (CRC). However, patients with a high expression of ERCC1 have a worse prognosis than those with a low expression. In this study, we investigated the effect of XPF-ERCC1 blockers on chemotherapy and 5-FU-based CRT and oxaliplatin (OXA)-based CRT in colorectal cancer cell lines. We investigated the half-maximal inhibitory concentration (IC50) of 5-FU, OXA, XPF-ERCC1 blocker, and XPF-ERCC1 blocker, and 5-FU or OXA combined and analyzed the effect of XPF-ERCC1 blocker on 5-FU-based CRT and oxaliplatin-based CRT. Furthermore, the expression of XPF and γ-H2AX in colorectal cells was analyzed. In animal models, we combined the XPF-ERCC1 blocker with 5-FU and OXA to investigate the effects of RC and finally combined the XPF-ERCC1 blocker with 5-FU- and oxaliplatin-based CRT. In the IC50 analysis of each compound, the cytotoxicity of the XPF-ERCC1 blocker was lower than that of 5-FU and OXA. In addition, the XPF-ERCC1 blocker combined with 5-FU or OXA enhanced the cytotoxicity of the chemotherapy drugs in colorectal cells. Furthermore, the XPF-ERCC1 blocker also increased the cytotoxicity of 5-FU-based CRT and OXA -based CRT by inhibiting the XPF product DNA locus. In vivo, the XPF-ERCC1 blocker was confirmed to enhance the therapeutic efficacy of 5-FU, OXA, 5-FU-based CRT, and OXA CRT. These findings show that XPF-ERCC1 blockers not only increase the toxicity of chemotherapy drugs but also increase the efficacy of combined chemoradiotherapy. In the future, the XPF-ERCC1 blocker may be used to improve the efficacy of 5-FU- and oxaliplatin-based CRT.

Update on Emerging Therapies for Advanced Colorectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy worldwide. It is projected to increase by 3.2 million new cases and account for 1.6 million deaths by 2040. Mortality is largely due to limited treatment options for patients who present with advanced disease. Thus, the development of effective and tolerable therapies is crucial. Chemotherapy has been the backbone of systemic treatment of advanced CRC, but utility has been limited because of invariable resistance to therapy, narrow mechanisms of action, and unfavorable toxicity profile. Tumors that are mismatch repair-deficient have demonstrated remarkable response to immune checkpoint inhibitor therapy. However, most CRC tumors are mismatch repair-proficient and represent an unmet medical need. Although ERBB2 amplification occurs only in a few cases, it is associated with left-sided tumors and a higher incidence of brain metastasis. Numerous combinations of HER2 inhibitors have demonstrated efficacy, and antibody-drug conjugates against HER2 represent innovative strategies in this area. The KRAS protein has been classically considered undruggable. Fortunately, new agents targeting KRAS G12C mutation represent a paradigm shift in the management of affected patients and could lead the advancement in drug development for the more common KRAS mutations. Furthermore, aberrant DNA damage response is present in 15%-20% of CRCs, and emerging innovative combinations with poly (ADP-ribose) polymerase (PARP) inhibitors could improve the current therapeutic landscape. Multiple novel biomarker-driven approaches in the management of patients with advanced CRC tumors are reviewed in this article.

Immunotherapy with Immune Checkpoint Inhibitors for Advanced Colorectal Cancer: A Promising Individualized Treatment Strategy

Colorectal cancer (CRC) is one of the high incident and lethal malignant tumors, and most of the patients are diagnosed at an advanced stage. The treatment of CRC mainly includes surgery, chemotherapy, radiotherapy and molecular targeted therapy. Despite these approaches have increased overall survival (OS) of CRC patients, the prognosis of advanced CRC remains poor. In recent years, remarkable breakthroughs have been made in tumor immunotherapy, especially immune checkpoint inhibitors (ICIs) therapy, bringing long-term survival benefits to tumor patients. With the increasing wealth of clinical data, ICIs have achieved significant efficacy in the treatment of high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) advanced CRC, but the therapeutic effects of ICIs on microsatellite stable (MSS) advanced CRC patients is currently unsatisfactory. As increasing numbers of large clinical trials are performed globally, patients treated with ICIs therapy also have immunotherapy-related adverse events and treatment resistance. Therefore, a large number of clinical trials are still needed to evaluate the therapeutic effect and safety of ICIs therapy in advanced CRC. This article will focus on the current research status of ICIs in advanced CRC and discuss the current predicament of ICIs treatment.

Notch-Jagged1 signaling and response to bevacizumab therapy in advanced colorectal cancer: A glance to radiomics or back to physiopathology?

The Notch intracellular domain (NICD) and its ligands Jagged-1(Jag1), Delta-like ligand (DLL-3) and DLL4 play an important role in neoangiogenesis. Previous studies suggest a correlation between the tissue levels of NICD and response to therapy with bevacizumab in colorectal cancer (CRC). Another marker that may predict outcome in CRC is radiomics of liver metastases. The aim of this study was to investigate the expression of NICD and its ligands and the role of radiomics in the selection of treatment-naive metastatic CRC patients receiving bevacizumab. Immunohistochemistry (IHC) for NICD, Jag1 and E-cadherin was performed on the tissue microarrays (TMAs) of 111 patients with metastatic CRC treated with bevacizumab and chemotherapy. Both the intensity and the percentage of stained cells were evaluated. The absolute number of CD4+ and CD8+ lymphocytes was counted in three different high-power fields and the mean values obtained were used to determine the CD4/CD8 ratio. The positivity of tumor cells to DLL3 and DLL4 was studied. The microvascular density (MVD) was assessed in fifteen cases by counting the microvessels at 20x magnification and expressed as MVD score. Abdominal CT scans were retrieved and imported into a dedicated workstation for radiomic analysis. Manually drawn regions of interest (ROI) allowed the extraction of radiomic features (RFs) from the tumor. A positive association was found between NICD and Jag1 expression (p< 0.001). Median PFS was significantly shorter in patients whose tumors expressed high NICD and Jag1 (6.43 months vs 11.53 months for negative cases; p = 0.001). Those with an MVD score ≥5 (CD31-high, NICD/Jag1 positive) experienced significantly poorer survival. The radiomic model developed to predict short and long-term survival and PFS yielded a ROC-AUC of 0.709; when integrated with clinical and histopathological data, the integrated model improved the predictive score (ROC-AUC of 0.823). These results show that high NICD and Jag1 expression are associated with progressive disease and early disease progression to anti VEGF-based therapy; the preliminary radiomic analyses show that the integration of quantitative information with clinical and histological data display the highest performance in predicting the outcome of CRC patients.

CO110 Systematic Literature Review (SLR) and Meta-Analysis (MA) of Clinical Outcomes for Second-Line and Higher (≥2L) Targeted Therapies for Advanced Colorectal Cancer (aCRC)

CO110 Systematic Literature Review (SLR) and Meta-Analysis (MA) of Clinical Outcomes for Second-Line and Higher (≥2L) Targeted Therapies for Advanced Colorectal Cancer (aCRC)

The Effective Role of Targeted Therapy in Advanced Colorectal Cancer

Though chemotherapy is the major strategy to manage patients with advanced-stage colorectal cancer (CRC), the main challenge is the progression of CRC despite using combination of different chemotherapeutic agents. So, to overcome this challenge, a new class&#x0D; Of therapy was developed naming “Targeted-therapy”. This class of drugs aim to target specific overexpressed or aberrant enzyme, receptor, or gene that have critical role in the growth and survival of colorectal cancerous cells. So that, by using combination of traditional strategy (chemotherapy) and targeted-drug, this will lead to improve survival and prevent the progression of advanced CRC

Precision medicine-based therapies in advanced colorectal cancer: The University of California San Diego Molecular Tumor Board experience.

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists. The MTB integrated molecular profiling information and patient characteristics to develop N‐of‐One treatments for 51 patients with advanced colorectal cancer. All patients had metastatic disease and 63% had received ≥ 3 prior therapy lines. Overall, 34/51 patients (67%) were matched to ≥ 1 drug recommended by the MTB based on individual tumor characteristics, whereas 17/51 (33%) patients received unmatched therapies. Patients who received matched therapy demonstrated significantly longer progression‐free survival (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21–0.81; P = 0.01) and a trend towards higher clinical benefit rates (41% vs. 18%, P = 0.058) (all multivariate) compared to patients receiving unmatched therapy. The MTB facilitated personalized matching of drugs to tumor characteristics, which was associated with improved progression‐free survival in patients with advanced colorectal cancer.

Adoptive T-Cell Therapy in Advanced Colorectal Cancer: A Systematic Review.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. For the vast majority of patients with advanced CRC (ie, for those in whom metastatic tumors are unresectable), treatment is palliative and typically involves chemotherapy, biologic therapy, and/or immune checkpoint inhibition. In recent years, the use of adoptive T-cell therapy (ACT), leveraging the body’s own immune system to recognize and target cancer, has become increasingly popular. Unfortunately, while ACT has been successful in the treatment of hematological malignancies, it is less efficacious in advanced CRC due in part to a lack of productive immune infiltrate. This systematic review was conducted to summarize the current data for the efficacy and safety of ACT in advanced CRC. We report that ACT is well tolerated in patients with advanced CRC. Favorable survival estimates among patients with advanced CRC receiving ACT demonstrate promise for this novel treatment paradigm. However, additional stage I/II clinical trials are needed to establish the efficacy and safety of ACT in patients with CRC.

A phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, in combination with other anticancer therapies in advanced colorectal cancer (CRC) and other solid tumors (CodeBreaK 101).

TPS214 Background: Approximately 3% of patients (pts) with CRC have the oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation. Sotorasib, a small molecule that specifically and irreversibly inhibits the KRAS G12C mutant protein, has demonstrated modest clinical activity and no dose-limiting toxicities as a single agent in heavily pretreated pts with KRAS p.G12C-mutated CRC. The combination of sotorasib with other anticancer therapies, such as EGFR or MEK inhibitors, may enhance antitumor efficacy and counteract potential escape mechanisms. Other attractive partners for sotorasib in CRC include biologics and chemotherapy combinations. The CodeBreaK 101 master protocol is designed to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple sotorasib-based combinations in pts with KRAS p.G12C mutated solid tumors. Key subprotocols with CRC combination treatment arms are highlighted here. Methods: This is a phase 1b, open-label study evaluating sotorasib alone and in combination regimens in pts with advanced KRAS p.G12C mutated CRC, NSCLC, and other solid tumors. Key regimens being explored in CRC include (1) Subprotocol A: Sotorasib + trametinib (MEK inhibitor) +/- panitumumab (EGFR inhibitor), (2) Subprotocol H: Sotorasib + panitumumab and sotorasib + panitumumab + FOLFIRI, and (3) Subprotocol M: Sotorasib + bevacizumab-awwb + FOLFIRI or FOLFOX. Key eligibility criteria include advanced or metastatic solid tumor with KRAS p.G12C mutation identified through molecular testing in treatment-naïve and pretreated patients depending on cohort. Primary endpoints include dose-limiting toxicities and treatment-emergent or treatment-related adverse events. Secondary endpoints include PK profile of combination regimens and efficacy (objective response, disease control, duration of response, time to response, and progression-free survival assessed per RECIST 1.1, and overall survival). Enrollment is ongoing. Contact Amgen Medical Information for more information: medinfo@amgen.com (NCT04185883). Abbreviations: EGFR = epidermal growth factor receptor; FOLFIRI = 5-fluorouracil + leucovorin + irinotecan; FOLFOX = 5-fluorouracil + leucovorin + oxaliplatin; MEK = mitogen-activated protein kinase. Clinical trial information: NCT04185883.

Study of PD-1 Customization and Autoimmune T Cells for Advanced Colorectal Cancer with High MSI Expression.

Objective To evaluate the significance of PD-1 customization and autoimmune T-cell therapy for advanced colorectal cancer with high MSI expression. Methods One hundred and eight patients with advanced colorectal cancer with high MSI expression admitted to our hospital between August 2019 and January 2022 were divided into control and study groups, and PD-1 customization and autoimmune T-cell therapy were administered to the two groups, respectively. Trends in immune indexes, PD-1 exposure, and survival rates were studied in both groups. Results The treatment efficiency of the study group was 90.74%, which was higher than that of the control group (61.11%) (P < 0. 05); after treatment, the presence of CDl07a, perforin, and GranB cells was significantly higher in both groups compared with that before treatment, but the expression of PD-1 was more pronounced in the study group (P < 0. 05); that is, the expression of PD-1 in peripheral T lymphocytes in the study group compared with that of the control group was higher in patients with grade III-IV, and peripheral T lymphocytes were also higher in patients with grade III-IV compared with patients with grade I-II (P < 0. 05). Conclusion PD-1 customization combined with autoimmune T-cell therapy is a novel therapeutic modality that can substantially improve.

Mesenchymal Stem Cell-Based Therapy For Advanced Colorectal Cancer: Potential Mechanisms Of Therapy And Associated Risks

Mesenchymal Stem Cell-Based Therapy For Advanced Colorectal Cancer: Potential Mechanisms Of Therapy And Associated Risks

Methylated DNA markers for monitoring palliative chemotherapy response in advanced colorectal cancer.

e15511 Background: Aberrantly methylated DNA marker (MDM) candidates are strongly associated with primary colorectal cancer (CRC) before treatment and detect CRC recurrence with high sensitivity when assayed from plasma. The relationship of these MDMs in association to chemotherapy treatment response is unknown. Methods: In a prospective cohort of patients receiving systemic therapy for advanced CRC, peripheral blood was collected serially during restaging visits. 15 patients were retrospectively identified to have partial response (PR), stable disease (SD) and progressive disease (PD) to treatment (n=5 for each group) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Using paired samples from each patient before and after response assessment, we analyzed 11 MDMs ( GRIN2D, ZNF671, ANKRD13B, QKI, VAV3, JAM3, SFMBT2, CHST2, ZNF568, FER1L4 and CNNM1) to assess correlation with treatment response. Cell-free DNA was extracted and bisulfite treated before MDMs were quantified by target enrichment long-probe quantitative-amplified signal assay and normalized to a methylated sequence of B3GALT6. Continuous variables are summarized as a median with corresponding interquartile ranges (IQR) and comparisons between subgroups were based on the Wilcox Rank Sums test. Results: The median interval between pre- and post-response assessment visits was 69 days (IQR: 63-83 days) and the level of tumor burden at pre-assessment was similar across all response types (Table 1). Patients with PD had higher levels of methylated GRIN2D, ZNF671 and ANKRD13B than those with PR or SD at baseline and may offer additional prognostic value over CEA which was similar in the PR and PD groups before treatment (Table 1). Elevation of pre-assessment MDMs preceded radiographic evidence of disease progression by 82 days (IQR 69-83 days). Conclusions: Three MDMs, GRIN2D, ZNF671 and ANKRD13B, were found to reflect treatment response (PD vs. PR + SD) as shown in the table. Although this pilot study was limited by a small sample size, it demonstrated the feasibility of using plasma-based MDMs in monitoring treatment response to systemic therapy for advanced CRC and should be compared to CEA in a larger study.[Table: see text]

A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint

Epigenetic therapies may modulate the tumor microenvironment. We evaluated the safety and optimal sequence of combination DNA methyltransferase inhibitor guadecitabine with a granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) using a primary endpoint of change in CD45RO + T cells. 18 patients with advanced CRC enrolled, 11 underwent paired biopsies and were evaluable for the primary endpoint. No significant increase in CD45RO + cells was noted. Grade 3–4 toxicities were expected and manageable. Guadecitabine + GVAX was tolerable but demonstrated no significant immunologic activity in CRC. We report a novel trial design to efficiently evaluate investigational therapies with a primary pharmacodynamic endpoint.Trial registry Clinicaltrials.gov: NCT01966289. Registered 21 October, 2013.

Oxaliplatin derived monofunctional triazole-containing platinum(II) complex counteracts oxaliplatin-induced drug resistance in colorectal cancer

Oxaliplatin-based chemotherapy is the current standard of care in adjuvant therapy for advanced colorectal cancer (CRC). But acquired resistance to oxaliplatin eventually occurs and becoming a major cause of treatment failure. Thus, there is an unmet need for developing new chemical entities (NCE) as new therapeutic candidates to target chemotherapy-resistant CRC. Novel Pt(II) complexes were designed and synthesized as cationic monofunctional oxaliplatin derivatives for DNA platination-mediated tumor targeting. The complex Ph-glu-Oxa sharing the same chelating ligand of diaminocyclohexane (DACH) with oxaliplatin but is equally potent in inhibiting the proliferation of HT29 colon cancer cells and its oxaliplatin-resistant phenotype of HT29/Oxa. The in vivo therapeutic potential of Ph-glu-Oxa was confirmed in oxaliplatin-resistant xenograft model demonstrating the reversibility of the drug resistance by the new complex and the efficacy was associated with the unimpaired high intracellular drug accumulation in HT29/Oxa. Guanosine-5′-monophosphate (5′-GMP) reactivity, double-strand plasmid DNA cleavage, DNA-intercalated ethidium bromide (EB) fluorescence quenching and atomic force microscopy (AFM)-mediated DNA denaturing studies revealed that Ph-glu-Oxa was intrinsically active as DNA-targeting agent. The diminished susceptibility of the complex to glutathione (GSH)-mediated detoxification, which confers high intracellular accumulation of the drug molecule may play a key role in maintaining cytotoxicity and counteracting oxaliplatin drug resistance.

Depletion of insulin-like growth factor 1 receptor increases radiosensitivity in colorectal cancer.

Although radiation therapy for advanced colorectal cancer (CRC) is very effective in some patients, treatment resistance limits its efficacy. Insulin-like growth factor 1 receptor (IGF1R) can affect tumor responsiveness and sensitivity to radiation in several cancer types. Herein, we studied the underlying function of IGF1R in the resistance of advanced CRC to radiation therapy and the possible use of drugs targeting IGF1R to overcome this resistance in patients with CRC. Differences in the expression levels of the IGF1R were assessed in CRC samples from patients who were radiosensitive or radioresistant. Two radio-resistant colorectal cancer cell lines, SW480 and HT29, were selected for in vitro studies, and the involvement of the IGF1R in their radiation resistance was elucidated by suppressing its expression through a targeted siRNA and through the use of a specific IGF1R inhibitor, BMS-754807. We assessed radiosensitivity in these human CRC cells lines by examining their proliferation and colony formation, as well as cell cycle analysis. Activation of the Akt pathway was assessed using western blotting. Compared with tissues from radiosensitive patients, higher IGF1R expression levels were found in patients with radiation-resistant colorectal cancer, while BMS-754807 had improved radiosensitivity and reversed radiation tolerance in both colorectal cancer cell lines. Pre-treatment with BMS-754807 prior to irradiation inhibited Akt phosphorylation, induced cell cycle arrest, and increased DNA damage. Therefore, the IGF1R contributes to radiation resistance of CRC cells in vitro. This study supports the notion that the radiosensitivity of radiation-resistant colorectal cancer cells can be enhanced by directly targeting IGF1R expression or activity. Ultimately, the combination of radiotherapy with IGF1R targeted inhibitors could potentially increase its effectiveness in the treatment of advanced colorectal cancer.