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Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer
Published in Shaker A. Mousa, Raj Bawa, Gerald F. Audette, The Road from Nanomedicine to Precision Medicine, 2020
Jiajia Zhang, Christopher L. Wolfgang, Lei Zheng
In pancreatic cancer, the average mutation burden was reported from 26~67 mutations per case [43, 44], representing a relatively low mutational burden compared to those seen in other solid tumors. In general, PDAC with more copy number alterations (indicative of chromosomal instability) exhibited mutations in DNA break repair genes and trended toward poor prognosis [43]. Microsatellite instability (MSI) and POLE/POLD1 mutations are found in 2% and 1–2% of patients with pancreatic cancer, respectively [45]. Favorable outcomes are anecdotally reported for MMR-deficient PDAC [46], suggesting that even lower incidence of MMR deficiency would be found in the PDAC patients who require treatment. A retrospective cohort study of resected PDAC (154 in discovery cohort and 95 in replication cohort) clustered PDAC into five predominant mutational subtypes: age related, double-strand break repair, mismatch repair, and one with unknown etiology. Those with higher frequency of somatic mutations and tumor-specific neoantigens corresponded to double-strand break repair and mismatch repair subtypes, which were found to have higher expression of antitumor immunity, including activation of CD8+ T lymphocytes and overexpression of regulatory molecules (CTLA-4, PD-1, and indolamine 2,3-dioxygenase 1 [IDO1]) [47]. Moreover, a significant number of germline mutations that are associated with genes for DNA repair were found in the double-strand break repair subtype including BRCA1, BRCA2, PALB2, and ATM. These gene mutations render individuals susceptible to pancreatic cancer and are potential biomarkers for response to targeted therapy or immunotherapy. Ongoing clinical trials are testing poly (ADP-ribose) polymerase (PARP) inhibitors in the small fraction of patients (<10%) with mutations in BRCA2 or other DNA repair genes.
Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer
Published in Shaker A. Mousa, Raj Bawa, Gerald F. Audette, The Road from Nanomedicine to Precision Medicine, 2019
Jiajia Zhang, Christopher L. Wolfgang, Lei Zheng
In pancreatic cancer, the average mutation burden was reported from 26~67 mutations per case [43, 44], representing a relatively low mutational burden compared to those seen in other solid tumors. In general, PDAC with more copy number alterations (indicative of chromosomal instability) exhibited mutations in DNA break repair genes and trended toward poor prognosis [43]. Microsatellite instability (MSI) and POLE/POLD1 mutations are found in 2% and 1–2% of patients with pancreatic cancer, respectively [45]. Favorable outcomes are anecdotally reported for MMR-deficient PDAC [46], suggesting that even lower incidence of MMR deficiency would be found in the PDAC patients who require treatment. A retrospective cohort study of resected PDAC (154 in discovery cohort and 95 in replication cohort) clustered PDAC into five predominant mutational subtypes: age related, double-strand break repair, mismatch repair, and one with unknown etiology. Those with higher frequency of somatic mutations and tumor-specific neoantigens corresponded to double-strand break repair and mismatch repair subtypes, which were found to have higher expression of antitumor immunity, including activation of CD8+ T lymphocytes and overexpression of regulatory molecules (CTLA-4, PD-1, and indolamine 2,3-dioxygenase 1 [IDO1]) [47]. Moreover, a significant number of germline mutations that are associated with genes for DNA repair were found in the double-strand break repair subtype including BRCA1, BRCA2, PALB2, and ATM. These gene mutations render individuals susceptible to pancreatic cancer and are potential biomarkers for response to targeted therapy or immunotherapy. Ongoing clinical trials are testing poly (ADP-ribose) polymerase (PARP) inhibitors in the small fraction of patients (<10%) with mutations in BRCA2 or other DNA repair genes.
Gold nanoparticles induce G2/M cell cycle arrest and enhance the expression of E-cadherin in breast cancer cells
Published in Inorganic and Nano-Metal Chemistry, 2020
Shaimaa Abdel-Ghany, Mennatallah Mahfouz, Nada Ashraf, Hussein Sabit, Emre Cevik, Mokhtar El-Zawahri
The Partner And Localizer of BRCA2 (PALB2) is a key protein that interacts with BRCA1 and BRCA2 and plays pivotal roles in homologous recombination (HR) DNA repair,[40] and its mutation is associated with increased breast cancer risk. PALB2 elevated expression was significantly associated with poorer overall survival (p < 0.01) in patients with stage III or nearby lymph node metastasis,[24] and it assume to play a role in cells too. In our study, exposing breast cancer cells to AuNPs resulted in downregulation of PALB2, and this was correlated also with decrease in the overall cell viability. This data could indicate that AuNPs could enforce cell suicide via suppression of PALB2. The expression of PALB2 is associated not only with familial type of BC, but also with sporadic type, as the absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% in patients with no family history of BC to 58% in those patients with two or more first-degree relatives with breast cancer at 50 years of age.[41]