Effective personalized therapy for breast cancer based on predictions of cell signaling pathway activation from gene expression analysis

Background: To study aniridia-related keratopathy (ARK) relevant cell signaling pathways (Notch1, Wnt/β-catenin, Sonic hedgehog (SHH) and mTOR) in normal human fetal corneas in comparison with normal human adult corneas. Results: 20 wg fetal and normal adult corneas showed similar staining patterns for Notch1, however 10-11 wg fetal corneas showed increased presence of Notch1. Numb and Dlk1 had an enhanced presence in the fetal corneas compared to the adult corneas. Fetal corneas showed stronger immunolabeling with antibodies against β-catenin, Wnt5a and Wnt7a, Gli1, Hes1, p-rpS6, and mTOR when compared to the adult corneas. Gene expression of Notch1, Wnt5A, Wnt7A, β-catenin, Hes1, mTOR and rps6 was higher in the 9-12 wg fetal corneas when compared to adult corneas. Conclusions: The cell signaling pathway differences found between human fetal and adult corneas were similar to those previously found in ARK corneas with the exception of Notch1. Analogous profiles of cell signaling pathway activation between human fetal corneas and ARK corneas suggests that there is a less differentiated host milieu in ARK.

Download Full-text

An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer

Breast Cancer Research ◽

10.1186/s13058-021-01408-9 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Erica M. Stringer-Reasor ◽

Jori E. May ◽

Eva Olariu ◽

Valerie Caterinicchia ◽

Yufeng Li ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Dna Repair ◽

Pilot Study ◽

Expression Analysis ◽

Triple Negative Breast Cancer ◽

Gene Expression Analysis ◽

Triple Negative ◽

Egfr Inhibition ◽

Link Type

Abstract Background Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. Methods A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. Results Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Conclusions Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. Trial registration ClinicalTrials.gov, NCT02158507. Registered on 12 September 2014

Download Full-text