Dormant or slow-cycling tumor cells can form a residual chemoresistant reservoir responsible for relapse in patients, years after curative surgery and adjuvant therapy. We have adapted the ...pulse-chase expression of H2BeGFP for labeling and isolating slow-cycling cancer cells (SCCCs). SCCCs showed cancer initiation potential and enhanced chemoresistance. Cells at this slow-cycling status presented a distinctive nongenetic and cell-autonomous gene expression profile shared across different tumor types. We identified TET2 epigenetic enzyme as a key factor controlling SCCC numbers, survival, and tumor recurrence. 5-Hydroxymethylcytosine (5hmC), generated by TET2 enzymatic activity, labeled the SCCC genome in carcinomas and was a predictive biomarker of relapse and survival in cancer patients. We have shown the enhanced chemoresistance of SCCCs and revealed 5hmC as a biomarker for their clinical identification and TET2 as a potential drug target for SCCC elimination that could extend patients' survival.
BRAF as a target for cancer therapy Dienstmann, Rodrigo; Tabernero, Josep
Anti-cancer agents in medicinal chemistry,
03/2011, Letnik:
11, Številka:
3
Journal Article
Recenzirano
Tumors with mutations in the gene encoding the serine-threonine protein kinase BRAF are dependent on the MAPK signaling pathway for their growth, what offers an opportunity to test oncogene-targeted ...therapy. Mutations at the position V600 of BRAF were described in approximately 8% of all solid tumors, including 50% of melanomas, 30 to 70% of papillary thyroid carcinomas and 5 to 8% of colorectal adenocarcinomas. Specific BRAF kinase inhibitors are undergoing rapid clinical development and promising data on efficacy have been demonstrated in activated mutant BRAF V600 melanomas. This review article will address: (a) preclinical data on the antitumor activity of BRAF inhibitors in cell lines/ in vivo models and their opposing functions as inhibitors or activators of the MAPK pathway, depending on the cellular context; (b) drug development from non-selective RAF inhibitors to selective BRAF inhibitors, such as PLX4032 and GSK2118436, with emphasis in the clinical efficacy and toxicity of these agents; and (c) possible mechanisms of resistance to BRAF inhibitors and strategies to overcome its development in BRAF mutant tumors.
The association of age at the onset of CRC and the prevalence of a
G12C mutation is unclear. A retrospective, multicenter study evaluating metastatic CRC patients from January 2019 to July 2023, ...treated at the Oncoclinicas units and tested for tissue based
/
and
mutations in a centralized genomics lab. A mismatch repair (MMR) status was retrieved from different labs and electronic medical records, as were patient demographics (age, gender) and tumor sidedness. The chi-square test was used to examine the association between clinical and molecular variables, with
value < 0.05 being statistically significant. A total of 858 cases were included. The median age was 63.7 years (range 22-95) and 17.4% were less than 50 years old at the diagnosis of metastatic CRC. Male patients represented 50.3% of the population. The sidedness distribution was as follows: left side 59.2%, right side 36.8% and not specified 4%. The prevalence of the
mutation was 49.4% and the
mutation was 3.9%. Among
mutated tumors, the most common variants were G12V (27.6%) and G12D (23.5%), while
G12C was less frequent (6.4%), which represented 3.1% of the overall population. The
mutant cases were 7.3% and most commonly V600E. Only five (<1%) non-V600E mutations were detected. MSI-high or dMMR was present in 14 cases (1.6%). In the age-stratified analysis, left-sidedness (
< 0.001) and a KRAS G12C mutation (
= 0.046) were associated with a younger age (<50 years). In the sidedness-stratified analysis, a
mutation (
= 0.001) and MSI-high/dMMR status (
= 0.009) were more common in right-sided tumors. Our data suggest that
G12C mutations are more frequent in early-onset metastatic CRC. To the best of our knowledge, this is the largest cohort in the Latin American population with metastatic CRC reporting
,
and MSI/MMR status.
AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in ...estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel.
Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.
Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in
/
and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in
or
, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding
from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of
p.E17K.
This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.
Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the ...proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.
Display omitted
•The cancer cell “co-variome” recapitulates functional protein associations•Loss-of-function mutations can impact protein levels beyond mRNA regulation•The consequences of genomic alterations can propagate through protein interactions•We provide insight into the molecular organization of colorectal cancer cells
Roumeliotis et al. use in-depth proteomics to assess the impact of genomic alterations on protein networks in colorectal cancer cell lines. Cell-line-specific network signatures are inferred de novo by protein quantification profiles and ultimately expose the collateral and transcript-independent effects of detrimental mutations on protein complexes.
Epidermal growth factor receptor (EGFR) is a validated target in different human malignancies. EGFR tyrosine kinase inhibitors (TKIs) are known to contribute considerably to the extension of ...progression-free survival in EGFR-mutant non-small cell lung cancer and monoclonal antibodies (mAbs) targeting EGFR have also improved the efficacy outcomes in KRAS wild-type colorectal cancer. Nevertheless, a significant percentage of lung and colorectal cancer patients do not respond to anti-EGFR agents and secondary resistance after initial benefit is a challenging reality faced by clinicians. Extensive preclinical work on the potential mechanisms of resistance to EGFR inhibitors in different disease settings has guided the development of second-generation irreversible EGFR TKIs, more efficient anti-EGFR mAbs, and combination strategies with agents targeting other receptors and downstream effectors. In order to elucidate the role of the multiple therapeutic strategies under investigation to overcome EGFR inhibitors-resistance, rational drug development based on stringent preclinical data, biomarker validation and proper selection of patients in the ongoing clinical trials are of paramount importance. Preliminary results of clinical trials evaluating these approaches will be discussed in this manuscript, with emphasis on TKIs in lung cancer and mAbs in advanced colorectal cancer.
CRC: colorectal cancer; EGFR: epidermal growth factor receptor; TKI: tyrosine kinase inhibitor; mAb: monoclonal antibody; IGF-1R: insulin-like growth factor 1 receptor; MET: mesenchymal–epithelial transition receptor; NSCLC: non-small cell lung cancer. Display omitted
► KRAS and secondary EGFR mutations confer resistance to EGFR inhibitors. ► Upregulation of parallel signaling pathways is a frequent adoptive response. ► Irreversible EGFR TKIs may overtake resistance in lung cancer. ► More efficient anti-EGFR mAbs are promising agents in colorectal cancer. ► Combination of targeted agents is a straightforward approach under investigation.
The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, ...pharmacodynamics, and antitumor activity of MEHD7945A.
Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3.
No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non-small cell lung cancer (n = 3).
MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer.
Of hundreds to thousands of somatic mutations that exist in each cancer genome, a large number are unique and non-recurrent variants. Prioritizing genetic variants identified via next generation ...sequencing technologies remains a major challenge. Many such variants occur in tumor genes that have well-established biological and clinical relevance and are putative targets of molecular therapy, however, most variants are still of unknown significance. With large amounts of data being generated as high throughput sequencing assays enter the clinical realm, there is a growing need to better communicate relevant findings in a timely manner while remaining cognizant of the potential consequences of misuse or overinterpretation of genomic information. Herein we describe a systematic framework for variant annotation and prioritization, and we propose a structured molecular pathology report using standardized terminology in order to best inform oncology clinical practice. We hope that our experience developing a comprehensive knowledge database of emerging predictive markers matched to targeted therapies will help other institutions implement similar programs.
•Annotation and prioritization of cancer gene variants is critical for clinical interpretation.•Actionable variants support treatment, enrolment in clinical trials and/or have prognostic/diagnostic implications.•Biologically relevant alterations should also be included in the reports of cancer genomic tests.•Structured reports with standardized vocabulary enable evidence-based decisions and matched targeted therapies.•A “knowledge database” with emerging preclinical/clinical predictive markers supports report generation.
Abstract
Chemotherapy-induced alopecia (CIA) is a challenge in the management of cancer patients. Scalp cooling (SC) leads to reduction in CIA, however it is associated with significant adverse ...events, leading to 3–13% discontinuation rates. This pilot study evaluated the role of Electric Hand Warmers (EHW) on thermal (TC), sensorial (SCo) and general comfort (GC) in patients with breast cancer (BC) undergoing chemotherapy and SC to reduce CIA. Patients were randomly assigned to EHW use or observation. TC, SCo and GC were evaluated after each chemotherapy infusion. Favorable outcomes in both TC and SCo defined a positive result on GC. We analysed the impact of age, alopecia, chemotherapy regimen and EHW use in the different comfort scales using a Logistic Regression (LR) model. Forty women with early breast cancer were randomly assigned to EHW (n = 20) or observation (n = 20) during neo(adjuvant) chemotherapy. Median age was 53 years. In the EHW arm, favorable thermal response was reported by 79% versus 50% in the control arm (odds ratio OR 3.79,
p
< 0.001). SCo was satisfactory in 82% in the EHW arm versus 74% in the control arm (OR 1.62,
p
= 0.1). Overall, 73% in the EHW arm had favorable GC versus 44% in the control arm (OR 3.4,
p
< 0.001). Age, alopecia, and chemotherapy regimen did not impact on comfort measures. Conclusion: Our study suggests that the use of an EHW has a consistent favorable impact on TC and GC of BC patients under SC technology to prevent CIA.
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