Project description:Radiotherapy is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. This study aimed to identify miRNAs associated with local relapse following radiotherapy.
Project description:Currently there is no predictive marker with clinical utility to guide treatment decisions in NSCLC patients undergoing radiotherapy. Identification of such markers would allow treatment options to be considered for more effective therapy. To enable the identification of appropriate protein biomarkers, plasma samples were collected from patients with non-small cell lung cancer before and during radiotherapy for longitudinal comparison following a protocol that carries sufficient power for effective discovery proteomics. Plasma samples from patients pre- and during radiotherapy who had survived >18 months were compared to the same time points from patients who survived <14 months using an 8 channel isobaric tagging tandem mass spectrometry discovery proteomics platform.
Project description:Background: MicroRNAs (miRNAs) are small, non-coding, RNA molecules which regulate numerous cellular processes. Specific miRNA may be abnormally down-regulated or up-regulated in colorectal cancer and have been found associated with prognosis or response to treatments. However, no study has ever addressed their predictive role in rectal cancer. Therefore, we used microarray technology and RT-PCR to profile miRNA expression patterns in patients (pts) with rectal cancer, with the aim to identify a specific M-bM-^@M-^\signatureM-bM-^@M-^] associated with pathological complete response after neoadjuvant chemo-radiotherapy. Methods: 38 pts with locally advanced rectal cancer (cT3-4/N+) were treated with capecitabine-oxaliplatin and pelvic conformal radiotherapy (45 cGy) followed by surgery (after 6-8 weeks). Pathologic response was scored according to the tumor regression grade (TRG) scale. MiRNA expression profile was analysed by microarray on fresh frozen biopsies obtained before treatment start and confirmed by RT-PCR. The correlation between miRNA expression profile and the TRG coded as TRG1 (pathologic Complete Response-pCR) versus TRG >1 (no pCR) was assessed by statistical analysis methods specifically designed for this study. Findings: 14 miRNAs were selected by arrays analysis as differentially expressed in TRG1 pts and 13 were confirmed by RT-PCR. In particular, 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909*, miR-630 and miR-765) were significantly up-regulated in TRG1 pts, while 2 miRNAs were under -expressed (miR-1274b and miR-720). miR-622 and miR-630 showed 100% sensitivity and specificity in selecting TRG1 cases and were significantly correlated with EGFR (M-OM-^G2=11M-bM-^@M-"793; p= 0M-bM-^@M-"001) and TS expression (M-OM-^G2=10M-bM-^@M-"589; p= 0M-bM-^@M-"001). Interpretation: A set of 13 miRNAs is strongly associated with pathologic complete response and may represent a specific marker of response to chemo-radiotherapy in locally advanced rectal cancer. Experiments were performed on purified RNA from preoperatory biopsies of 38 patients with histological diagnosis of rectal adenocarcinoma invading through the intestinal wall and/or with pelvic lymph node involvement as evaluated by endorectal ultrasonography (uT3-T4 and/or uN+). Patients were treated with neoadjuvant chemo-radiotherapy (capecitabine + oxaliplatin in combination with 45 Gy of pelvic conformal radiotherapy). Patients have been divided in the following two groups: group A those who had obtained a pathologic complete response M-bM-^@M-^S TRG 1, including the patient without detectable disease who refused surgery, group B any pathologic response other than complete.
Project description:PurposeRadiotherapy is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced radiotherapy technologies enable treatment with large fractions and highly conformal radiation doses to effect free-radical damage to cellular DNA leading to cell-cycle arrest, cell death, and innate immune response (IIR) stimulation.Experimental designTo understand systemic clinical responses after radiation exposure, proteomic and metabolomic analyses were performed on plasma obtained from patients with cancer at intervals after prostate stereotactic body radiotherapy. Pathway and multivariate analyses were used to delineate molecular alterations following radiotherapy and its correlation with clinical outcomes.ResultsDNA damage response increased within the first hour after treatment and returned to baseline by 1 month. IIR signaling also increased within 1 hour of treatment but persisted for up to 3 months thereafter. Furthermore, robust IIR and metabolite elevations, consistent with an early proinflammatory M1-mediated innate immune activation, were observed in patients in remission, whereas patients experiencing prostate serum antigen-determined disease progression demonstrated less robust immune responses and M2-mediated metabolite elevations.ConclusionsTo our knowledge, these data are the first report of longitudinal proteomic and metabolomic molecular responses in patients after radiotherapy for cancers. The data supports innate immune activation as a critical clinical response of patients receiving radiotherapy for prostate cancer. Furthermore, we propose that the observed IIR may be generalized to the treatment of other cancer types, potentially informing multidisciplinary therapeutic strategies for cancer treatment.
Project description:gene expression profiling of locally invasive breast carcinomas treated with preoperative radiotherapy the purose of this study was to establish molecular signature associated with response to radiotherapy using radiotherapy-naïve biopsies of locally advanced breast cancer
Project description:Genome wide DNA methylation profiling of human blood samples. The Illumina Infinium EPIC DNA methylation Beadchip was used to obtain DNA methylation profiles Survival has increased in early stage breast cancer (BC), and the late effects of cancer treatment can persist for decades. The molecular mechanisms underlying acceleration of age-related diseases after chemotherapy and radiotherapy are poorly understood. We examined epigenetic changes in peripheral blood in early stage BC patients undergoing either adjuvant radiotherapy, or adjuvant chemotherapy and radiotherapy. DNA methylation experiments were performed on peripheral blood samples from women collected prior to and following completion of adjuvant therapy. Methylation profiles were used to estimate three measures of epigenetic age acceleration - intrinsic, extrinsic, and phenotypic - as well as estimated cell counts.
Project description:We employed our recently developed proteogenomic workflow (De Marchi et al, 2021) to analyze a cohort of 21 primary breast cancers by RNA sequencing and mass spectrometry.
Project description:Analysis of 80 glioblastoma specimen of patients treated within clinical trials and 4 samples of "normal" brain tissue (non-tumoral). The data was used to identify factors of resistance to a chemoradiation therapy protocol of radiotherapy and concomitant and adjuvant temozolomide (alkylating agent). Experiment Overall Design: 80 glioblastoma specimen and 4 non-tumoral brain samples
Project description:This study explores the safety and efficacy of combining topical Imiquimod (IMQ), a TLR-7 agonist, with local radiotherapy (RT) for metastatic breast cancer. The phase I/II clinical trial (NCT01421017) aimed to assess systemic and local anti-tumor responses using immune-related response criteria (irRC). Patients were divided into three cohorts: (1) IMQ + RT + cyclophosphamide, (2) IMQ + RT, and (3) RT + cyclophosphamide (control). Cutaneous metastases were treated with IMQ+RT (area A) or IMQ alone (area B). Tumor biopsies were obtained at baseline and after treatment for gene expression profiling. Results demonstrated safety and promising systemic anti-tumor responses, with transcriptional analyses revealing a T-helper 1 immune orientation and DNA-repair gene downregulation associated with complete responses in IMQ+RT-treated areas.