scholarly journals Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6018
Author(s):  
Marlen Keil ◽  
Theresia Conrad ◽  
Michael Becker ◽  
Ulrich Keilholz ◽  
Marie-Laure Yaspo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Growth ◽  
Predictive Biomarkers ◽  
Drug Combinations ◽  
Tumor Growth Inhibition ◽  
Complete Regression ◽  
Targeted Drugs ◽  
Metastatic Colon Cancer ◽  
Current Standard ◽  
Combination Scheme

The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Background for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs.

Telotristat ethyl to enhance cytotoxic chemotherapy response in preclinical cholangiocarcinoma models.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 331-331
Author(s):  
Niranjan Awasthi ◽  
Margaret Schwarz ◽  
Roderich E. Schwarz
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Peritoneal Dissemination ◽  
Primary Liver Cancer ◽  
Tumor Growth Inhibition ◽  
Chemotherapy Response ◽  
Current Standard ◽  
First Line Therapy ◽  
Survival Studies

331 Background: Cholangiocarcinoma (CCA) is the second-most common primary liver cancer after hepatocellular carcinoma. It has a poor prognosis with a 5-year survival rate of 5-15%. The current standard first-line therapy for advanced unresectable CCA is a combination of gemcitabine and cisplatin (GemCis) chemotherapy that leads to a median survival of 6-12 months. Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel, NPT) is an approved therapy for breast, NSCLC and pancreatic cancer. Elevated levels of serotonin have been reported in CCA that has protumorigenic activity. We tested the hypothesis that telotristat ethyl (TE), an inhibitor of serotonin biosynthesis, has antitumor activity in CCA and it augments GemCis and nab-paclitaxel response in preclinical CCA models. Methods: Tumor growth experiments were performed in mice subcutaneous CCA intrahepatic CCLP-1 xenografts, extrahepatic TFK-1 xenografts and patient-derived xenografts. Animal survival studies were performed using human CCA intrahepatic CCLP-1 cells in the peritoneal dissemination model in NOD/SCID mice. Results: In intrahepatic CCLP-1 subcutaneous xenografts, compared with controls, reduction in tumor growth was observed by TE (53%), GemCis (53%) or NPT (69%). The combination of TE with GemCis or NPT exhibited an additive tumor growth inhibition response, GemCis+TE (85%) and NPT+TE (90%). In extrahepatic TFK-1 subcutaneous xenografts, TE led to a significant reduction in tumor growth (51%), while GemCis and NPT reduced tumor growth by 37% and 56%, respectively. Again, an additive tumor growth inhibition effect was observed by the addition of TE to chemotherapy, GemCis+TE (67%) and NPT+TE (74%). In CCA patient-derived subcutaneous xenografts, GemCis caused the greatest tumor growth reduction (80%) followed by NPT (57%) and TE (40%). Combinations increased tumor inhibition further: GemCis+TE (95%) and NPT+TE (91%). Mouse survival in peritoneal dissemination xenografts was only marginally enhanced by TE (11%) or GemCis (9%) while NPT led to a substantial extension (60%). Interestingly, the combination of TE with GemCis or NPT demonstrated a further extension in mice survival: GemCis+TE (26%) and NPT+TE (68%). Conclusions: TE had antitumor activity and it enhanced chemotherapy effects in several CCA preclinical models indicating that this therapeutic combination has the potential to ameliorate clinical therapy for CCAs of different origin.

scholarly journals ERCC1 and TS Expression as Prognostic and Predictive Biomarkers in Metastatic Colon Cancer

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0126898 ◽  
Author(s):  
Michel B. Choueiri ◽  
John Paul Shen ◽  
Andrew M. Gross ◽  
Justin K. Huang ◽  
Trey Ideker ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Predictive Biomarkers ◽  
Metastatic Colon Cancer

scholarly journals Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 379 ◽  
Author(s):  
María Belén Ortega-García ◽  
Alberto Mesa ◽  
Elisa L.J. Moya ◽  
Beatriz Rueda ◽  
Gabriel Lopez-Ordoño ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Chemotherapy Response ◽  
Metastatic Colon Cancer ◽  
First Line ◽  
Expression Levels ◽  
End Point ◽  
Line Chemotherapy

Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients’ data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data.

The Bcl-2 Family Inhibitor ABT-263 Shows Significant Anti-Tumor Efficacy in Models of B Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 825-825
Author(s):  
Alex R. Shoemaker ◽  
Michael J. Mitten ◽  
Anatol Oleksijew ◽  
Jacqeuline M. O’Connor ◽  
Baole Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
B Cell ◽  
Cell Lymphoma ◽  
Cytotoxic Agents ◽  
Tumor Growth Inhibition ◽  
Complete Regression ◽  
Mantle Cell

Abstract ABT-263 is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins with a Ki of ≤ 1 nM against Bcl-2, Bcl-XL, and Bcl-w. Non-Hodgkin’s B-cell lymphomas represent clinically relevant disease targets for this molecule due, in part, to strong expression of Bcl-2 often associated with various types of NHL (frequently involving a t(14;18) translocation including the Bcl-2 locus). ABT-263 exhibits sub-micromolar in vitro activity against a variety of NHL cell lines. DoHH-2 and WSU-DLCL2 are two B-cell NHL lines harboring the t(14;18) translocation that exhibit differential in vitro sensitivity to ABT-263. Granta-519 is a mantle cell lymphoma line with the characteristic t(11;14)(q13:q32) translocation resulting in overexpression of cyclin D1. ABT-263 has an EC50 of approximately 150 nM in the Granta-519 cell line. Here we present efficacy data evaluating the activity of ABT-263 in several NHL xenograft models. ABT-263 has significant in vivo anti-tumor efficacy in established flank tumor models both as monotherapy and in combination with cytotoxic agents. The efficacy of ABT-263 at 100 mg/kg/day, p.o., q.d. ×21 was evaluated as monotherapy and in combination with etoposide, vincristine, modified CHOP, R-CHOP, bortezomib, rapamycin, and rituximab. Results show that ABT-263 significantly inhibits tumor growth as a monotherapy (~50–60% tumor growth inhibition) and enhances the efficacy of these cytotoxic agents in combination therapy. Statistically significant enhancement of tumor growth inhibition was observed for each combination relative to monotherapy treatment. Efficacy was maintained even when therapy was initiated on larger (~500 mm3) tumors. Combinations of ABT-263 + rapamycin and ABT-263 + rituximab result in complete regression of a significant percentage of established B cell lymphoma tumors for a sustained period of time in vivo. The combination of ABT-263 + R-CHOP resulted in complete regression of 100% of the tumors in the mantle cell lymphoma model. The strong in vitro potency and tumor regressions seen in vivo suggest that ABT-263 has great potential for the oral treatment of NHL B-cell lymphomas.

The anticancer effects of supinoxin (RX-5902) in pancreatic carcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 238-238 ◽  
Author(s):  
Young Lee ◽  
Reza Mazhari ◽  
Deog Joong Kim
Keyword(s):  
Tumor Growth ◽  
Pancreatic Carcinoma ◽  
Cell Lines ◽  
Cancer Therapeutics ◽  
Breast Cancer Cell Lines ◽  
Growth Delay ◽  
Tumor Growth Inhibition ◽  
High Dose ◽  
Complete Regression ◽  
Mesenchymal Transition

238 Background: DEAD box RNA helicase DDX5/p68, and its phosphorylated form in particular, may play several important roles in cancer by means of cell transformation, epithelial mesenchymal transition (EMT), and cell migration, deeming it a promising target for novel anti-cancer therapeutics. We have previously shown that Supinoxin (RX-5902) interacts with phosphorylated p68 on Tyr593, interfering with the phosphorylated p68-β-catenin signaling pathway. Supinoxin also inhibits motility of MDA-MB231 breast cancer cell lines and could potentially prevent metastasis in cancer. Methods: In this study, we first demonstrated anti-proliferative effects in several cell lines originated from pancreas (5 cell lines) with a high level of sensitivity to Supinoxin (IC50 of 18 nM). We also sought to examine the tumor growth inhibition (TGI) and/or tumor growth delay (TGD), and survival benefits of Supinoxin in the human pancreatic carcinoma (MiaPaCa-2) xenograft mouse model. Results: In the MiaPaCa-2 model, at 50 and 70 mg/kg daily (oral, 5 days on/2 days off) for 3 weeks, both doses delayed tumor growth significantly (83% and 339%; P < 0.001). All animals in the high dose showed complete regression (CR) and completing the study as tumor free survival (TFS; Day 65); one animal showed CR and TFS in the lower dose. Gemcitabine (120 mg/kg ip; Q3D for 4 weeks) resulted in TGD of 71% (P < 0.001), with no CRs. Supinoxin did not result in a reduction in body weight gain, treatment related deaths, or clinical observations in this tumor model. Conclusions: These data support the potential therapeutic activity of Supinoxin in pancreatic cancer. A Phase 1 study of Supinoxin on relapse/refractory solid tumors is ongoing (NCT02003092).

scholarly journals CHEMOTHERAPY IN THE MANAGEMENT OF LOCALIZED AND METASTATIC COLON CANCER: NEW AND YET UNFORGOTTEN APPROACHES

2017 ◽  
pp. 67-76
Author(s):  
N. V. Dobrova ◽  
O. O. Gordeeva ◽  
E. V. Chernoglazova ◽  
A. A. Tryakin
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Life Expectancy ◽  
Metastatic Colorectal Cancer ◽  
Surgical Resection ◽  
Targeted Drugs ◽  
Metastatic Colon Cancer ◽  
The Past ◽  
New Approaches

Over the course of the past couple of decades, we have witnessed some significant improvements in the treatment of metastatic colorectal cancer: the emergence of novel targeted drugs and a differentiated approach to their administration, the extension of indications for surgical resection for liver and lungs metastases has resulted in the increased life expectancy among patients in this group. Nevertheless, chemotherapy remains the treatment of choice for colon cancer. In this paper, we discuss new approaches to the use of chemotherapy on stages III and IV of colorectal cancer.

The effect of copper nanoparticles on the progression of tumor in vivo.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3084-3084 ◽  
Author(s):  
Polina Sergeevna Kachesova ◽  
Irina Aleksandrovna Goroshinskaya ◽  
Vladimir Borisovich Borodulin
Keyword(s):  
Tumor Growth ◽  
Copper Nanoparticles ◽  
Male Rats ◽  
Control Group ◽  
Entire Group ◽  
Tumor Growth Inhibition ◽  
Complete Regression ◽  
Fusiform Cell ◽  
Sarcoma 45

3084 Background: The study of the anticancer activity of copper nanoparticles (CuNP) measuring 70-75 nm in rats transplantable tumors. Methods: Experiments were carried out on white outbreed male rats with transplanted sarcoma 45 (9.10-dimethyl-1.2-benzanthracene-induced fusiform cell fibrosarcoma, S-45) and Pliss’s lymphosarcoma (Pliss). 0.5 ml of tumor tissue suspension (1x106 cells) in saline was inoculated subcutaneously in rat dorsal region for induction of sarcoma 45 or Pliss's lymphosarcoma. 7-8 days after tumors transplantation the animals were divided into three groups. Group 1: control (rats received 0.3 ml of saline only). Group 2: CuNP in 0.9% w/v of NaCl were injected intratumorally (1.25 mg/kg bodyweight). Group 3: The same amount of CuNP was injected intraperitonially. Animals received nanoparticles four times a week for one week, then after a week's break, the procedure was repeated. The associated nanoparticles are spherical in shape and have an oxide film on its surface. CuNP effect on tumor growth was determined by the mass (M) and size (V) of tumors. Results: The analysis of the received data showed that administration of CuNP to rats with S-45 caused reduced growth rates or cases with complete regression (8 of 17 cases) in 67.0% of experimental animals independently of injection way (V=0.81±0.3 cm3, M=0.91±0.3 g). The other 33% of rats with S-45 showed tumor growth (V=7.58±1.3 cm3, M=9.2±1.6 g). Overall, for the entire group of animals with S-45, nanoparticles inhibited tumor growth of 45%. In the control group there was an increase of tumor growth (V=9.0±1.8 cm3, M=10.4±2.5 g). CuNP introduction to animals with Pliss caused a delay in tumor growth and partial or complete regression (12 of 28 eight cases) in 40.0-48.0% of the rats in the route of Cu injection (V=1.4±0.8 cm3, M=10.4±2.5g). Observation of the remaining animals revealed tumor growth (V=60.6±5.93 cm3, M=67.13±8.7 g). In the whole group tumor growth inhibition was 50.0%. In the control group we observed increase of tumor growth (V=62.1±5.21 cm3, M=75.9±8.2 g). Conclusions: Thus the study showed that the copper nanoparticles possess antiproliferative activity, can inhibit the growth of transplanted tumors in rats and may be potentially used in anticancer medical therapy.

Rational combination therapy in young vs older patients with advanced colorectal cancer (CRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 612-612
Author(s):  
Anna Capasso ◽  
Todd M. Pitts ◽  
John J. Tentler ◽  
Peter J Klauck ◽  
Stacey M Bagby ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Older Patients ◽  
Single Agent ◽  
Young Patients ◽  
Predictive Biomarkers ◽  
Tumor Growth Inhibition ◽  
Sequencing Analysis ◽  
Younger Patients ◽  
Risk Of Death ◽  
Pdx Models

612 Background: Although CRC is rare in young adults, the incidence has increased recently and patients present more commonly with Stage III or IV disease which may reflect differing biology. Prior analyses revealed a statistically significant increase in the risk of death in young patients with metastatic CRC compared to older patients. Methods: To assess age-dependent genetic changes, DNA and RNA from younger ( < 40) and older ( > 65) CRC were isolated, and whole exome and transcriptome sequencing analysis from 4699 FFPE CRC clinical specimens were performed. Hybridization capture was performed on up to 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Samples were sequenced to high (average 688X) uniform coverage. CRC PDXs were injected into athymic nude mice and randomized into vehicle control, refametinib (MEKi), OMP-18R5 (monoclonal Ab against FZD 1, 2, 5, 7, and 8), or the combination and treated for at least 28 days. Results: Gene alteration rates in the younger and older cohorts were similar in a majority of the genes analyzed. Alterations in CTNNB1 [p < 0.001, False Discovery Rate (FDR) = 0.07] and MLH1 (p < 0.001, FDR = 0.017) were found to be more common in younger patients. Older patients were more likely to have alterations in APC (p < 0.01, FDR < 0.01) and FAM123B (p < 0.01, FDR = 0.03). The CTNNB1 data provided support to explore the WNT pathway as a potential target for younger patients. Therefore, we conducted an in vivo study of MEKi and OMP-18R5 to assess efficacy in molecularly defined young CRC PDX models. In a young PDX models, we observed enhanced combination effects with tumor growth inhibition index (treated/control) of 13% in the combination arm (compared to tumor growth of 150 %, and 116%, respectively with MEKi and OMP-18R5 alone). Interestingly, in this PDX models, RNA sequencing data showed baseline enrichment in the WNT and mTOR pathway, not observed in the older PDX models. Conclusions: The combination of refametinib and OMP-18R5 showed enhanced antitumor activity in combination compared to the single agent arms. Studies investigating predictive biomarkers of response are currently underway.

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