One-shot dual gene editing for drug-resistant pancreatic cancer therapy

Won, Eun-Jeong; Park, Hyeji; Chang, Simyung; Kim, Jin Hyun; Kwon, Hee Uk; Cho, Young Seok; Yoon, Tae‐Jong

doi:10.1016/j.biomaterials.2021.121252

Cited by 8 publications

(12 citation statements)

References 35 publications

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“…In addition to the KRAS mutations observed in 90% of patients with PDAC, mutations in the tumor suppressor gene P53 are also observed in 50–80% of patients. Moreover, about 55% of patients have both KRAS and P53 mutations, which lead to an increase in glucose metabolites, including deoxycytidine triphosphate (dCTP) [ 58 ]. dCTP can be inserted into DNA strands for replication and will compete with the active metabolite of GEM in the nucleus, thus making PDAC resistant to GEM.…”

Section: Well-designed Nanosystems For Different Pdac Therapeuticsmentioning

confidence: 99%

Recent Advances in Well-Designed Therapeutic Nanosystems for the Pancreatic Ductal Adenocarcinoma Treatment Dilemma

Yang

et al. 2023

Molecules

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Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with an extremely poor prognosis and low survival rate. Due to its inconspicuous symptoms, PDAC is difficult to diagnose early. Most patients are diagnosed in the middle and late stages, losing the opportunity for surgery. Chemotherapy is the main treatment in clinical practice and improves the survival of patients to some extent. However, the improved prognosis is associated with higher side effects, and the overall prognosis is far from satisfactory. In addition to resistance to chemotherapy, PDAC is significantly resistant to targeted therapy and immunotherapy. The failure of multiple treatment modalities indicates great dilemmas in treating PDAC, including high molecular heterogeneity, high drug resistance, an immunosuppressive microenvironment, and a dense matrix. Nanomedicine shows great potential to overcome the therapeutic barriers of PDAC. Through the careful design and rational modification of nanomaterials, multifunctional intelligent nanosystems can be obtained. These nanosystems can adapt to the environment’s needs and compensate for conventional treatments’ shortcomings. This review is focused on recent advances in the use of well-designed nanosystems in different therapeutic modalities to overcome the PDAC treatment dilemma, including a variety of novel therapeutic modalities. Finally, these nanosystems’ bottlenecks in treating PDAC and the prospect of future clinical translation are briefly discussed.

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Section: Well-designed Nanosystems For Different Pdac Therapeuticsmentioning

confidence: 99%

Recent Advances in Well-Designed Therapeutic Nanosystems for the Pancreatic Ductal Adenocarcinoma Treatment Dilemma

Yang

et al. 2023

Molecules

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“…However, boosted by the unparalleled simplicity and convenience, CRISPR-Cas9 system has become the most prevelantly used GET at present. Moreover, since genome editing can be leveraged for the disruption or correction of oncogenes [41,42], reprogramming of anti-cancer immune cells [43], and establishment of cancer models [44], it emerge as a powerful and versatile tool in the development of anticancer therapies.…”

Section: Genome Editing In the Development Of Personalized Anti-cance...mentioning

confidence: 99%

Genome editing via non-viral delivery platforms: current progress in personalized cancer therapy

et al. 2022

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Cancer is a severe disease that substantially jeopardizes global health. Although considerable efforts have been made to discover effective anti-cancer therapeutics, the cancer incidence and mortality are still growing. The personalized anti-cancer therapies present themselves as a promising solution for the dilemma because they could precisely destroy or fix the cancer targets based on the comprehensive genomic analyses. In addition, genome editing is an ideal way to implement personalized anti-cancer therapy because it allows the direct modification of pro-tumor genes as well as the generation of personalized anti-tumor immune cells. Furthermore, non-viral delivery system could effectively transport genome editing tools (GETs) into the cell nucleus with an appreciable safety profile. In this manuscript, the important attributes and recent progress of GETs will be discussed. Besides, the laboratory and clinical investigations that seek for the possibility of combining non-viral delivery systems with GETs for the treatment of cancer will be assessed in the scope of personalized therapy.

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“…CRISPR-Cas13a system reduces mRNA expression in mammalian cells and shows an improved efficacy and specificity over RNA interference [60,61]. The system reduced the KRAS G12D mRNA expression with up to 70% knockdown efficiency (Figure 4b-d Recently, our group has developed a tumor targeted-nanoliposome (NL[Cas9/ABE]-Ab) that simultaneously encapsulates CRISPR/Cas9 and adenine-base editor (ABE) proteins for dual-gene editing (Figure 5) [15]. The Cas9 and ABE proteins are modified with his-tag protein to improve NL-encapsulation efficiency.…”

Section: Pre-assembled Ribonucleoprotein (Rnp) Complex Deliverymentioning

confidence: 99%

“…NL(Cas9/ABE)-Ab inhibits KRAS and TP53 mutations, and regulates HIF-1α-related glycolysis, which promotes gemcitabine sensitivity in vivo (Figure 5d-f). Therefore, the dual-gene editing tool of the KRAS mutation and mutant TP53 might overcome drug-resistance in PDAC [15].…”

Section: Pre-assembled Ribonucleoprotein (Rnp) Complex Deliverymentioning

confidence: 99%

“…In this review, we present RNA interference (RNAi)-based therapeutics using nanomedicine-based delivery systems that are currently being investigated in clinical trials for the treatment of PDAC. Recently, we developed a novel therapeutic strategy that targets KRAS and TP53 mutations at same time via liposome delivery of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), ribonucleoprotein (RNP) complexes, and single-guide RNA (sgRNA) to overcome drugresistance of PDAC, and this treatment significantly enhanced the anti-tumor activity of gemcitabine [15]. In addition, current advances in the application of genome editing technology to PDAC research are reviewed.…”

Section: Introductionmentioning

confidence: 99%

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Gene Therapy Using Nanocarriers for Pancreatic Ductal Adenocarcinoma: Applications and Challenges in Cancer Therapeutics

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and its incidence is increasing. PDAC often shows resistance to several therapeutic modalities and a higher recurrence rate after surgical treatment in the early localized stage. Combination chemotherapy in advanced pancreatic cancer has minimal impact on overall survival. RNA interference (RNAi) is a promising tool for regulating target genes to achieve sequence-specific gene silencing. Here, we summarize RNAi-based therapeutics using nanomedicine-based delivery systems that are currently being tested in clinical trials and are being developed for the treatment of PDAC. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing has been widely used for the development of cancer models as a genetic screening tool for the identification and validation of therapeutic targets, as well as for potential cancer therapeutics. This review discusses current advances in CRISPR/Cas9 technology and its application to PDAC research. Continued progress in understanding the PDAC tumor microenvironment and nanomedicine-based gene therapy will improve the clinical outcomes of patients with PDAC.

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One-shot dual gene editing for drug-resistant pancreatic cancer therapy

Cited by 8 publications

References 35 publications

Recent Advances in Well-Designed Therapeutic Nanosystems for the Pancreatic Ductal Adenocarcinoma Treatment Dilemma

Recent Advances in Well-Designed Therapeutic Nanosystems for the Pancreatic Ductal Adenocarcinoma Treatment Dilemma

Genome editing via non-viral delivery platforms: current progress in personalized cancer therapy

Gene Therapy Using Nanocarriers for Pancreatic Ductal Adenocarcinoma: Applications and Challenges in Cancer Therapeutics

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