scholarly journals The potential of miR-630, an IGF1R regulator, as a predictive biomarker for HER2-targeted drugs.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 620-620
Author(s):  
Claire Corcoran ◽  
Sweta Rani ◽  
Susan Breslin ◽  
Irene M. Ghobrial ◽  
John Crown ◽  
...  
Keyword(s):  
Cell Lines ◽  
Potential Role ◽  
Acquired Resistance ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Targeted Drugs ◽  
Anoikis Resistance ◽  
Her2 Positive ◽  
Resistant Phenotype ◽  
In Cells

620 Background: Innate or acquired resistance to current HER-targeting drugs indicates that their use for HER2-overexpressing breast cancer (BC) treatment may be compromised. miRNAs may have potential as diagnostic, prognostic and predictive biomarkers for treatment response, as well as therapeutic targets and replacement therapies. We aimed to investigate miR-630 as a predictive biomarker for response to a range of HER-drugs and as a potential target for increasing sensitivity to the same. Methods: Following global miRNA profiling using taqman low density arrays, the reduced expression of miR-630 in cells and corresponding conditioned medium (CM) of HER2-positive BC cell lines with acquired/innate lapatinib (L) resistance (SKBR3-LR, HCC1954-LR, MDA-MB-453) was confirmed by qPCR. miR-630 mimics and inhibitors were used to assess cell response to current (L, trastuzumab (T)) and emerging (neratinib (N), afatinib (A)) HER-targeting drugs. Targetscan prediction software and immunoblotting were used to determine miR-630 regulated proteins. Results: miR-630 levels were significantly decreased in cells and CM with acquired lapatinib resistance compared to their age-matched controls. Decreased miR-630 was also observed for innately resistant MDA-MB-453 compared to innately sensitive SKBR3.Administration of miR-630 mimic significantly sensitised resistant cells to all 4 drugs tested. Specifically, miR-630 mimic increased the anti-proliferative effects of L by 31% (SKBR3-LR), 9% (HCC1954-LR) and 9% (MDA-MB-453). Similarly, miR-630 mimic improved the efficacy of T (11-35%), N (4-17%) and A (9-25%); (range for different cell lines). Inhibition of miR-630 in sensitive parent cells induced an insensitive/resistant phenotype, significantly reducing the efficacy of all 4 drugs tested. Interestingly, miR-630 also significantly regulates cell motility, invasion and anoikis resistance implicating this miRNA in overall cell aggressiveness. Conclusions: This data suggests a potential role for miR-630 as a predictive biomarker for HER-targeting drugs as well as an additional therapeutic target for HER2-overexpressing BC. Acknowledgements: MTCI SFI SRC (08/SRC/B1410), MKF and HEA’s PRTLI Cycle 5 to TBSI.

scholarly journals Neuromedin U: A potential predictive biomarker for HER2-targeted drugs.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 617-617
Author(s):  
Sweta Rani ◽  
Serena Germano ◽  
Stephen F. Madden ◽  
Claire Corcoran ◽  
Susan Breslin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Predictive Biomarker ◽  
Targeted Drugs ◽  
Breast Cancer Patients ◽  
Anoikis Resistance ◽  
Her2 Positive ◽  
Over Expression ◽  
Knock Down ◽  
Poor Outcome ◽  
Resistant Cells

617 Background: Not all HER2-positive breast cancer patients respond to HER2-targeted drugs and some, who initially respond, subsequently relapse. There is a need to identify biomarkers for improved patient selection. Here we aimed to identify gene expression changes associated with response to HER2-targeted drugs. Methods: To identify mRNA changes associated with resistance, whole genome microarrays were used to profile conditioned medium (CM) from HER2-positive cell lines (SKBR3, HCC1954) and their lapatinib (L)-resistant variants (SKBR3-LR, HCC1954-LR). Neuromedin U (NmU) over-expression, identified in this way, was confirmed in the L-resistant cells and corresponding CM by qPCR and ELISA. Pooled data from 21 published expression datasets (n=3489 patients) was mined to relate NmU mRNA to tumour subtype and patients' outcome. NmU cDNA and siRNAs were used to over-express and knock-down expression of NmU, respectively, prior to assessing it’s association with response to L, Trastuzumab (T) and Neratinib (N). Results: Analysis of the tumour data showed NmU expression to be particularly associated with poor outcome for patients with HER2-positive tumours (p=0.000005). In cell lines, we identified NmU mRNA and protein to be at significantly higher levels in L-resistant cells and corresponding CM, compared to that of L-sensitive SKBR3 and HCC1954. This trend was observed for T-resistant and N-resistant SKBR3 cells (SKBR3T, SKBR3N) and their CM, compared to sensitive parent SKBR3 cells and CM. NmU cDNA over-expression in SKBR3 and HCC1954 increased resistance to L, T and N. Knock-down of NmU endogenous levels in SKBR3-LR and innately L-resistant MDA-MB-361 and T47D sensitised these cells to L, T and N. Further analysis of our NmU over-expressing and knock-down cells indicated NmU to also be associated with increased motility, invasion and anoikis resistance. Conclusions: NmU expression is prognostic of poor outcome in HER2-positive breast tumours. In cell line models, NmU over-expression is associated with resistance to L, T and N. Taken together, we propose NmU as a possible prognostic and predictive biomarker for HER2-positive cancers, with potential also as a co-target to help circumvent resistance to these drugs. [SFI: 08/SRC/B1410]

scholarly journals RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

2021 ◽  
Author(s):  
Olav Engebraten ◽  
Christina Yau ◽  
Kristian Berg ◽  
Elin Borgen ◽  
Oystein Garred ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Intracellular Transport ◽  
Kinase Inhibitors ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Cytotoxic Agents ◽  
Endocytic Trafficking ◽  
Trastuzumab Emtansine ◽  
Her2 Positive

PURPOSE: Targeted therapeutics strongly depends on validated biomarkers in order to select patients most likely to benefit from the treatment. HER2 serves as a predictive biomarker for HER2-targeted tyrosine kinase inhibitors and monoclonal antibodies. HER2 may, however, also be utilized as a transport gate for delivery of cytotoxic agents into the cell, such as for HER2-targeted antibody drug conjugates (ADCs; e.g. trastuzumab emtansine (T-DM1)). The predictive biomarkers for such ADCs may be more complex, also reflecting the intracellular transport. METHODS: Five HER2-positive breast and ovarian cancer cell lines were evaluated with respect to T-DM1 sensitivity and correlated to the expression levels of proteins involved in endocytic trafficking including RAB4A, RAB5A and RAB11A, with possible impact on ADC pharmacology. The results were confirmed in a clinical cohort consisting of patients from the adaptive breast cancer clinical trial I-SPY2 where pathological complete response (pCR) was correlated to the RNA expression level of RAB4A, RAB5A and RAB11A. A subset of the clinical KAMILLA trial including 19 patients was used as a verification cohort where semi-quantitative IHC of RAB5A was correlated to progression free survival (PFS). RESULTS: The early endosome marker RAB5A, was found to correlate positively to T-DM1 sensitivity in the cell line panel. Correlation between RAB5A expression and T-DM1 sensitivity (pCR) was confirmed in patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial, but not in the trastuzumab/paclitaxel control arm. The clinical correlation was verified in the patients from the KAMILLA trial where semi- quantitative RAB5A IHC staining correlated significantly positive to PFS. CONCLUSION: The present results indicate that RAB5A is a predictive biomarker for T-DM1 and outline, for the first time, proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

scholarly journals RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Olav Engebraaten ◽  
Christina Yau ◽  
Kristian Berg ◽  
Elin Borgen ◽  
Øystein Garred ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Transport ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Cytotoxic Agents ◽  
Trastuzumab Emtansine ◽  
Targeted Therapeutics ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Drug Conjugates

AbstractHER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody–drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

Early predictors of benefit to dual anti-PD1/HER2 inhibition: Biomarker analysis from phase 2 trial of pembrolizumab/trastuzumab in HER2-positive metastatic esophagogastric (mEG) cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4058-4058
Author(s):  
Steven Brad Maron ◽  
Walid Khaled Chatila ◽  
Henry S. Walch ◽  
Ryan Ptashkin ◽  
Shalom Sabwa ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Ct Scans ◽  
Her2 Positive ◽  
Phase 2 Trial ◽  
Biomarker Analysis ◽  
Pre Treatment ◽  
Pet Scans

4058 Background: Pembrolizumab and trastuzumab (P&T) and chemotherapy demonstrated 27 month mOS, 13 month mPFS, and 91% response rate in first-line HER2-positive mEG cancer irrespective of PD-L1 status (Janjigian Lancet Oncology 2020). Biomarkers including 89Zr-trastuzumab PET, blood, and tumor analysis were correlated with progression-free survival. Methods: Twenty-five patients received P&T once 3 weeks prior to addition of chemotherapy to P&T. Pre-treatment tumor biopsies, 89Zr-trastuzumab PET scans, serial plasma ctDNA (Guardant360, Redwood City, CA) and CT scans were performed. Tumor-matched DNA alterations were identified by correlating ctDNA and tissue-NGS variant calls. Pre-, on-, and post-treatment biopsies were analyzed using WES and IHC (HER2, PD-L1). Biomarkers were correlated with mPFS and 6-month PFS, the primary endpoint. Results: Of patients with tumor-matched mutations ctDNA at baseline, 12 of 16 had a decline in their maxVAF by week 3, corresponding to a mPFS of 14.7 (11.0-NR) vs 5.9 (95% CI 4.1-NR) months (p=0.009) and a mOS of 29.7 (95% CI 27.2-NR) vs 7.71 (95% CI 6.6-NR) months (p=0.006). 9 of 12 (75%) patients with decline in ctDNA at 3 weeks post-P&T achieved the 6-month PFS primary endpoint while the 4 patients with no decline in ctDNA all progressed in under 6-months. Similarly, 7 of 9 (78%) patients who had a decline in CT-measurements in all disease sites achieved the 6 month PFS primary endpoint, versus 10 of 16 (62.5%) of patients who did not respond in all sites (p=0.66), suggesting that ctDNA is superior to CT as an early predictive biomarker of response. Lack of ERBB2 amplification (amp) by NGS in ctDNA and/or tumor was associated with lack of response to P&T alone prior to addition of chemotherapy. Interestingly, no lesions from patients lacking ERBB2 ctDNA amp (n=3) responded to induction P&T by CT, while lesions from 3/9 patients lacking ERBB2 tissue amp responded to P&T by 3-week CT, suggesting intrapatient HER2 heterogeneity. Eight patients also underwent 89Zr-Trastuzumab PET scans prior to P&T and up to 5 lesions per disease site were measured on serial CT scans. All 15 lesions with intense uptake (SUVmax>10) responded to P&T, but only 9/24 lesions with SUVmax<10. All 4 patients who had at least 1 intense lesion achieved a post-P&T CT response and later 6+ month PFS. All 3 of 3 evaluable patients with intense uptake had baseline ctDNA ERBB2 amp. Conclusions: Patients with a decline in tumor-matched maxVAF after one dose of P&T were more likely to achieve durable PFS. Pre-treatment ctDNA ERBB2 amp and/or intense 89Zr-trastuzumab PET avidity are non-invasive predictive biomarkers of response to HER2-directed therapy. Evaluation of tumor immune environment digital spatial profiling is underway. Clinical trial information: NCT02954536.

Measurements of Mcl-1 protein dependencies using dimerization-specific antibodies as predictive biomarkers for BH-3 mimetic class therapies in AML.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19505-e19505
Author(s):  
Michael H. Cardone ◽  
Andrew Kinloch ◽  
Mine Canakci ◽  
Jingping Ge
Keyword(s):  
Cell Lines ◽  
Protein Complexes ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Response To Treatment ◽  
Clinical Settings ◽  
Cancer Therapies ◽  
Protein Levels ◽  
Combination Treatments

e19505 Background: The anti-apoptotic Bcl-2 family proteins facilitate pro-survival and resistance to anti-cancer therapies. Measuring the function of these proteins has shown utility in predicting response to treatment. A biomarker platform that assesses the functionality of these proteins by measuring BH3 mediated signaling potential in individual patients’ cancers, could provide a potential guiding platform for treating AML. In AML venetoclax is becoming widely prescribed and highly effective in combination with other drugs. Recent data indicate that Mcl-1 dependence is a resistance factor to venetoclax and that methods for identifying this could provide guidance for combination treatments. We are developing a technology to directly measure the occurrence of heterodimers of Mcl-1, or Bcl-xL, bound to pro-apoptotic BH3-only protein Bim. These measurements are combined in algorithms developed to indicate the cancer cell apoptotic priming state and offer great potential for identifying best AML treatment options. Methods: Monoclonal antibodies against conformation-specific epitopes induced in Mcl-1/Bim and Bcl-xL/Bim protein complexes were made. Selective bonding of Heterodimer Specific Mcl-1 Bim (HSMCB) and Heterodimer Specific Bcl-xL Bim (HSBXB) mabs were confirmed using ELISA, fluorescence polarization, immunofluorescence microscopy and flow, and by immunohistochemistry in genetically defined cell lines and in AML patient biopsied samples. Results: We show that HSMCB signal depends on both Mcl-1 and Bim protein levels while HSBXB requires Bc-xL and Bim levels. The relative signals of HSMCB to unbound Mcl-1 signal ([HsMcB]/[Mcl-1]) provide a biomarker for Mcl-1 dependence. We carefully established binding metrics that correlate to drug response in cell lines. The pharmacological disruption of these complexes is monitored by the ratiometric readouts that serve as predictive biomarkers for BH-3 mimetic drugs in AML cells. Conclusions: Mcl-1 dependence is a predictive biomarker for venetoclax resistance and for response to Mcl-1 targeted therapies. Flow cytometric and IHC based measurements of a heterodimer complex offer a direct and simpler approach that harbors potential for use in clinical settings. Additional antibodies targeting Mcl-1/Bak and Bcl-2/Bim complexes are being tested.

scholarly journals Expression Atlas of FGF and FGFR Genes in Pancancer Uncovered Predictive Biomarkers for Clinical Trials of Selective FGFR Inhibitors

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yuan Li ◽  
Long Wu ◽  
Weiping Tao ◽  
Dawei Wu ◽  
Fei Ma ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Tumor Cell ◽  
Cell Lines ◽  
Expression Profiles ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Tumor Cell Lines ◽  
Expression Atlas ◽  
Tumor Types

Background. Clinical trials based on FGFR mutation or amplification as a druggable target of FGFR inhibitors have produced disappointing clinical outcomes. Therefore, the identification of predictive biomarkers for FGFR-targeted agents has remained a crucial issue. Methods. Expression profiles of FGFs and FGFRs in 8,111 patients with 24 types of solid tumors and 879 tumor cell lines along with drug sensitivity data were obtained and followed by integrative bioinformatics analysis. Results. FGFs and FGFRs were frequently dysregulated in pancancer. Most of the expression of FGFs and FGFRs were significantly associated with overall survival in at least two cancer types. Moreover, tumor cell lines with high FGFR1/3 expression were more sensitive to FGFR inhibitor PD173074, especially in breast, liver, lung and ovarian cancer. The predicted positive ratios of FGFR1-4 were generally over 10% in most tumor types, especially in squamous cell carcinoma. High positive FGFR1 or 3 expression ratios were predicted in cholangiocarcinoma (58%), followed by bladder cancer (42%), endometrial carcinoma (35%), and ovarian cancer (34%). Conclusions. FGFR expression was a promising predictive biomarker for FGFR inhibition response in clinical trials, and different combinations of FGFR genes should be used in screening for patients in certain tumor types.

scholarly journals CTNI-17. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii45-ii46
Author(s):  
Abed Rahman Kawakibi ◽  
Rohinton S Tarapore ◽  
Sharon Gardner ◽  
Chase Thomas ◽  
Rodrigo Cartaxo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Cancer ◽  
Resistance Mechanism ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Clinical Analysis ◽  
Mechanism Analysis ◽  
Human Cancer Cell Lines ◽  
Best Response ◽  
Diffuse Midline Glioma

Abstract Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation rarely survive longer than two years and have no proven therapies following first-line radiation. ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in early phase studies in H3 K27M-mutant DMG. In order to define response rates in H3 K27M DMG patients and to clarify the genomic, anatomic and molecular predictors of response, we performed an integrated pre-clinical and clinical analysis of ONC201 treatment. ONC201 was effective in intra-uterine electroporation (IUE)-generated H3 K27M-mutant murine glioma models with excellent CNS penetration and survival benefit. Patients with H3 K27M-mutant DMG treated with ONC201 on active clinical trials (n=50, 27 thalamic, 23 brainstem) showed an overall survival (OS) of 28.1 (range: 5.9–105) months from diagnosis (enrollment by 4/29/19, data cut-off 12/28/19), compared to historical median OS of 12 months. Median OS for non-recurrent patients has not been reached (n=16, median follow-up: 16.8 from diagnosis). For non-recurrent thalamic patients (n=8), median PFS is 20.1 (range: 9.3–27.6) months from diagnosis (median time on drug: 14.5 months). Best response for thalamic patients by RANO: 1 CR, 5 PR, 7 SD, 8 PD, 6 not reported. Decreased H3 K27M cell-free tumor DNA in plasma and CSF at 6 months correlated with long-term response. Baseline tumor gene expression profiling in patients treated with ONC201 (n=14) identified EGFR and the cortical developmental transcription factor FOXG1 as the strongest biomarkers of radiographic response to ONC201. Analysis of 541 ONC201-treated human cancer cell lines from DepMap, provided evidence for an EGFR-dependent ONC201 resistance mechanism. Analysis of 38 glioma cell lines further supports FOXG1 as a glioma-specific predictive biomarker of ONC201 response. The unprecedented survival results and radiographic responses to ONC201 in H3K27M DMG make a compelling case for later phase and combinatorial studies.

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