Advanced Phase I/II Studies of Targeted Gene Delivery In Vivo: Intravenous Rexin-G for Gemcitabine-resistant Metastatic Pancreatic Cancer

Chawla, Sant P.; Chua, Victoria S.; Fernández, L.; Quon, Dorris; Blackwelder, William C.; Gordon, Erlinda M.; Hall, Frederick L.

doi:10.1038/mt.2009.228

Cited by 70 publications

(69 citation statements)

References 27 publications

(36 reference statements)

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“…In particular, the retroviral transfer of the cytocidal N-terminal truncated cyclin G1 (Rexin-G) did not give any evidence of efficacy in one trial [59] but seemed to have a dose-dependent response in another trial (Table 1) [60].…”

Section: Clinical Trials Completed and Ongoingmentioning

confidence: 99%

“…One of the trials is still recruiting and the results are not available. Two other trials reported during the American Society of Clinical Oncology (ASCO) conferences in 2011 displayed encouraging results that will probably lead to phase II studies (Table 1) [60]. Noticeably however, preclinical studies showed that GCV/TK treatment can lead to resistance, probably because some of transferred genes can be lost a while after the beginning of the treatment [61,62].…”

Section: Clinical Trials Completed and Ongoingmentioning

confidence: 99%

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Gene Therapy of Pancreatic Cancer

Dabernat¹,

Lafitte²,

Bedel³

et al. 2013

J Genet Syndr Gene Ther

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a 5-year survival rate of less than 5%. The poor prognosis of the disease is associated with late diagnosis and a high degree of drug resistance has not been overcome during the past decades. Gemcitabine-based regimens are the first line therapy for advanced pancreatic cancer but are not curative. Recent new combination chemotherapies achieved significant benefits but toxicity makes their use controversial. Novel approaches are currently being developed; in particular cancer gene therapies are undergoing preclinical and clinical validation and are the topic of the present review. We will present different ways to design gene therapy against pancreatic cancers that have been validated in preclinical studies. We also reviewed the clinical trials already published or still ongoing.Citation: Dabernat S, Lafitte M, Bedel A, de Verneuil H, Moreau-Gaudry F (2013) Gene Therapy of Pancreatic Cancer. J Genet Syndr Gene Ther 4: 138. doi:10.4172/2157-7412.1000138 Page 2 of 6Volume 4 • Issue 4 • 1000138 Suicide Gene Therapy of Cancer J Genet Syndr Gene Ther ISSN: 2157-7412 JGSGT, an open access journal gene restoration efficiency [12]. Restoring a wild type SMAD4 did not always block tumor cells [13] rendering the use of this tumor suppressor controversial [14]. Many oncogenes can be deregulated and/or mutated in pancreatic cancers. Among them, mutations in the KRAS oncogene occur in almost all pancreatic adenorcinomas [9]. Thus, it is tempting to use direct anti-KRAS strategies to inhibit tumor growth (Figure 1b), since disappointing results have been obtained with inhibition of farnesyl transferases [1]. RNAi directed against mutated KRAS showed anti-tumor activity [15], limited the aggressive phenotype of the tumor cells [16] and potentiated gemcitabine antitumor activity [17]. Preclinical studies showed encouraging results with viral delivery systems such as oncolytic adenovirus [18]. However, this strategy has not been further tested in phase I clinical trials.In fact, pancreatic adenocarcinomas present very complex genetic alterations profiles. The Pancreatic Cancer Genome project has analyzed 23,219 transcripts and identified an average of 63 somatic mutations per PDAC affecting 12 core signaling pathways and the overexpression of 500 different genes in 24 tumors [19]. These highly versatile and unpredictable molecular patterns can explain the failure of single gene/pathway targeted adjuvant therapies. It is now critical to test therapies targeting several pathways or therapies that induce specific tumor cell death. Delivering a Suicide GeneWith the suicide gene approach, a gene that encodes a protein triggering tumor cell death is delivered to the tumor cells ( Figure 1c). The expression of the therapeutic gene can directly kill the cells (diphtheria toxin, [20]), or can render the cells sensitive to certain otherwise non toxic prodrugs (Gene Directed Enzyme Prodrug Therapy, GDEPT,[21]), or based on gemcitabine association ...

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Section: Clinical Trials Completed and Ongoingmentioning

confidence: 99%

Section: Clinical Trials Completed and Ongoingmentioning

confidence: 99%

Gene Therapy of Pancreatic Cancer

Dabernat¹,

Lafitte²,

Bedel³

et al. 2013

J Genet Syndr Gene Ther

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“…rungs of the pharmacological dose-response curve for Stage IV pancreatic cancer (Galanis et al, 2008) compared to the higher, more-effective doses shown in succeeding advanced Phase I/II studies (shown in Figure 11; Chawla et al, 2010). Meanwhile, clinical development of Rexin-G advanced in the Philippines through a series of Phase I/II studies and an Expanded Access program, which extended the scope of clinical applications to a wider variety of cancers, including breast cancer, melanoma, and laryngeal CA (Gordon et al, 2006.…”

Section: Thementioning

confidence: 99%

Critical Stages in the Development of the First Targeted, Injectable Molecular-Genetic Medicine for Cancer

Gordon¹,

Hall²

2011

Gene Therapy Applications

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“…In clinical studies, Rexin-G has demonstrated significant anti-tumor activity in a number of solid tumor types, including breast, colon, lung, skin, muscle and bone, as well as pancreas cancer (11,12). Following on from initial Phase I safety studies (13) and adaptive Phase I/II studies (14,15), Rexin-G was granted Orphan Drug Status by the US FDA in 2008 for both soft tissue sarcoma and osteosarcoma, in addition to pancreatic cancer. Advanced Phase I/II clinical studies of Rexin-G for pancreatic cancer have shown that Rexin-G is well-tolerated, with an excellent safety/toxicity profile, and its repeated administration is associated with significant tumor regression and prolonged progression-free survival, with strong indications that Rexin-G monotherapy may improve overall survival as well (15).…”

Section: Introductionmentioning

confidence: 99%

“…Following on from initial Phase I safety studies (13) and adaptive Phase I/II studies (14,15), Rexin-G was granted Orphan Drug Status by the US FDA in 2008 for both soft tissue sarcoma and osteosarcoma, in addition to pancreatic cancer. Advanced Phase I/II clinical studies of Rexin-G for pancreatic cancer have shown that Rexin-G is well-tolerated, with an excellent safety/toxicity profile, and its repeated administration is associated with significant tumor regression and prolonged progression-free survival, with strong indications that Rexin-G monotherapy may improve overall survival as well (15). Following rigorous evaluations of the safety and efficacy of Rexin-G administered as stand-alone therapy for a broad spectrum of otherwise intractable cancers, Rexin-G was formally approved for the treatment of all chemotherapy-resistant solid tumors in the Republic of the Philippines, and has more recently been granted Fast Track status, as well as Orphan Drug priorities, by the US FDA.…”

Section: Introductionmentioning

confidence: 99%

Noteworthy clinical case studies in cancer gene therapy: Tumor-targeted Rexin-G advances as an efficacious anti-cancer agent

Гордон¹

2010

Int J Oncol

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Abstract. The advent of pathotropic (disease-seeking) targeting technology has ushered cancer gene therapy across the threshold of history, marking the beginning of a new epoch of medical praxis. For the first time, clinical oncologists can reach beyond the finest of catheters, beyond the reach of the most gifted surgeons, to the very fabric of metastatic disease in an effort to halt the progression and turn the tide of otherwise intractable cancers. The enabling molecular biotechnologies embodied in the leading tumor-targeted agent, Rexin-G, and its timely development as a safe and effective anti-cancer drug -from oncogene discovery and target validation, to molecular engineering of the core nanotechnologies, to the first clinical proofs-of principle, confirmatory trials, expanded access programs, and accelerated regulatory approvals -have been extensively documented in the medical literature. Therefore, this paper represents a final chapter, highlighting a series of noteworthy cases studies in the emergent field of targeted genetic medicine: case studies which, in and of themselves, reveal vital and important aspects of the molecular-genetic bio-pharmacology, advanced clinical protocols, refinement of patient monitoring, expanding treatment options, and strategic medical approaches to patient care that exemplify and thereby extend the established principles of pathotropic targeting and cancer gene therapy to a new generation of clinical practitioners.

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Advanced Phase I/II Studies of Targeted Gene Delivery In Vivo: Intravenous Rexin-G for Gemcitabine-resistant Metastatic Pancreatic Cancer

Cited by 70 publications

References 27 publications

Gene Therapy of Pancreatic Cancer

Gene Therapy of Pancreatic Cancer

Critical Stages in the Development of the First Targeted, Injectable Molecular-Genetic Medicine for Cancer

Noteworthy clinical case studies in cancer gene therapy: Tumor-targeted Rexin-G advances as an efficacious anti-cancer agent

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