Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation–associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day

Current Status of CRISPR/Cas9 Application in Clinical Cancer Research: Opportunities and Challenges

Cancer is considered by not only multiple genetic but also epigenetic amendments that drive malignant cell propagation and consult chemo-resistance. The ability to correct or ablate such mutations holds enormous promise for battling cancer. Recently, because of its great efficiency and feasibility, the CRISPR-Cas9 advanced genome editing technique has been extensively considered for therapeutic investigations of cancers. Several studies have used the CRISPR-Cas9 technique for editing cancer cell genomic DNA in cells and animal cancer models and have shown therapeutic potential in intensifying anti-cancer protocols. Moreover, CRISPR-Cas9 may be used to correct oncogenic mutations, discover anticancer drugs, and engineer immune cells and oncolytic viruses for immunotherapeutic treatment of cancer. We herein discuss the challenges and opportunities for translating therapeutic methods with CRISPR-Cas9 for clinical use and suggest potential directions of the CRISPR-Cas9 system for future cancer therapy

The role of variants of homologous recombination repair genes in breast cancer susceptibility and DNA repair

Apart from being the most common malignancy in women worldwide, breast cancer is also one of the most extensively investigated human cancers. The breast cancer susceptibility genes, BRCA1 and BRCA2 are responsible for less than 10% of breast cancer cases. However the genetic basis of the majority of breast cancer has not yet been identified. Since an acquired genetic instability resulting from the defects in DNA repair is known to promote tumorigenesis, a proportion of inherited breast cancers might be attributable to mutations in the genes involved in these functions. Homologous Recombination Repair (HRR) is an accurate and high fidelity repair mechanism, which is mainly responsible for repair of DNA double strand breaks (DSBs). There is considerable evidence to suggest that defects in DNA damage repair in particular in HRR contribute to breast cancer. In the present study we tested the effect of single nucleotide polymorphisms of HRR genes on breast cancer susceptibility. We screened a series of 522 breast cancer patients and 900 healthy controls for a panel of four polymorphic HRR genes. The rare allele of XRCC2 R188H was found to be associated with increased risk of breast cancer (odds ratio: 1.32, CI: 0.98,1.79). This allele was also shown to be more associated with lobular breast carcinoma (p=0.001). Furthermore there was preliminary evidence of interaction between XRCC2 R188H and XRCC3 T241 M, and also between XRCC3 T241 M and BRCA2 N372H alleles (both p=0.06). Four novel naturally occurring sequence variants of the XRCC3 DNA repair gene were also identified. We studied the effect of these sequence variants on the repair ability of the XRCC3 protein. A rare XRCC3 variant (D213N), was shown to completely ablate the protein function. The association of this variant with cancer susceptibility was studied in a group of 1524 patients with common cancer and 1577 healthy individuals. However, no association between this variant and cancer susceptibility was found, indicating that XRCC3 is unlikely to be a tumour suppressor gene. The results from the present study support the hypothesis that normally occurring variation in DNA repair genes can influence DNA repair capacity and cancer susceptibility in the population

A Proposal for a National Cancer Control Plan for the UAE: 2022–2026

The United Arab Emirates (UAE) is one of the fastest growing economies with consequent increase in non-communicable diseases including cancer. The number of reported cases and mortality have been increasing in the UAE over the years, despite screening and early detection efforts which appear to be far from target coverage of the intended population. In this work, we highlight key elements of a proposed national cancer control plan for the UAE. The plan is still a work in progress and has not yet been officially adopted. A comprehensive and effective control plan requires accurate data, a reliable cancer registry, and periodic monitoring and evaluation. The UAE cancer control plan is being prepared in line with the WHO and EMRO framework, with defined objectives and goals. The objectives are to combat cancer, reduce incidence, control mortality, and improve outcomes and quality of life for cancer patients. There is also a focus on improving public health education, prevention, early detection, prompt diagnosis, treatment facilitation, continuity of care, performance evaluation, training of workforce, and research

Current Status of CRISPR/Cas9 Application in Clinical Cancer Research: Opportunities and Challenges

Cancer is considered by not only multiple genetic but also epigenetic amendments that drive malignant cell propagation and consult chemo-resistance. The ability to correct or ablate such mutations holds enormous promise for battling cancer. Recently, because of its great efficiency and feasibility, the CRISPR-Cas9 advanced genome editing technique has been extensively considered for therapeutic investigations of cancers. Several studies have used the CRISPR-Cas9 technique for editing cancer cell genomic DNA in cells and animal cancer models and have shown therapeutic potential in intensifying anti-cancer protocols. Moreover, CRISPR-Cas9 may be used to correct oncogenic mutations, discover anticancer drugs, and engineer immune cells and oncolytic viruses for immunotherapeutic treatment of cancer. We herein discuss the challenges and opportunities for translating therapeutic methods with CRISPR-Cas9 for clinical use and suggest potential directions of the CRISPR-Cas9 system for future cancer therapy

Unrestricted somatic stem cells, as a novel feeder layer: Ex vivo culture of human limbal stem cells

Ex vivo culture of limbal stem cells (LSCs) is a current promising approach for reconstruction of the ocular surface. In this context, 3T3 feeder layer cells (mouse embryo fibroblast) are generally utilized to maintain and expand LSCs. The aim of this study is to develop a novel culture method (animal-derived products free) to expand LSCs, using umbilical cord derived human unrestricted somatic stem cells (hUSSCs) instead of 3T3 cell with an emphasis on maintaining of the Stemness in LSCs. Using flow-cytometer, isolated hUSSCs were characterized for CD105, CD90, CD166, CD34, CD45, CD31 cell surface markers and their differentiation capability into adipogenic as well as osteogenic lineages were evaluated. In addition to colony-forming efficiency (CFE), epithelial lineage differentiation and karyotyping, LSC properties were evaluated for ABCG2, ΔNP63-α, CK19, CK3, and CK12 mRNA and protein expressions using quantitative RT-PCR (qRT-PCR) and immunocytochemistry, when these cells were co-cultured with hUSSCs (in comparison with 3T3 feeder layer). LSCs, co-cultured with hUSSCs, showed normal karyotype (46, XX), while they could efficiently form colony (86 ± 3) and display up-regulation of the genes associated with stemness and down-regulation of corneal epithelial differentiation genes. Consistent with 3T3 feeder cells, hUSSCs with spindle-shaped morphology and quick splitting up properties had ability to preserve the stem like-cell phenotype of LSCs. These findings were confirmed by qRT-PCR and flow-cytometer. Findings of present study suggest hUSSCs as a promising alternative method for 3T3 feeder layer cells, to preserve growth and stemness of LSCs ex vivo culture