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Nemunaitis J.,Mary Crowley Cancer Research Centers
Expert Opinion on Therapeutic Targets | Year: 2012

Stathmin 1 (STMN1) is a critical protein involved in microtubule polymerization and is necessary for survival of cancer cells. This editorial describes the role of targeted therapeutics which disrupt STMN1 modulation and such effect on cancer survival. © Informa UK, Ltd. Source

Wu J.X.,University of California at Los Angeles | Liu S.-H.,University of California at Los Angeles | Nemunaitis J.J.,Mary Crowley Cancer Research Centers | Brunicardi F.C.,University of California at Los Angeles
Cancer Letters | Year: 2015

PDX1 is overexpressed in pancreatic cancer, and activates the insulin promoter (IP). Adenoviral IP-thymidine kinase and ganciclovir (TK/GCV) suppresses human pancreatic ductal carcinoma (PDAC) in mice, but repeated doses carry significant toxicity. We hypothesized that multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity compared to adenoviral IP-TK/GCV. SCID mice with intraperitoneal human pancreatic cancer PANC-1 tumor implants were given a single cycle of 35 μg iv L-IP-TK, or four cycles of 1, 10, 20, 30, or 35 μg iv L-IP-TK (n = 20 per group), followed by intraperitoneal GCV. Insulin and glucose levels were monitored in mice treated with four cycles of 35 μg iv L-IP-TK. We found that four cycles of 10-35 μg L-IP-TK/GCV ablated more PANC-1 tumor volume compared to a single cycle with 35 μg. Mice that received four cycles of 10 μg L-IP-TK demonstrated the longest survival (. P < 0.05), with a median survival of 126 days. In comparison, mice that received a single cycle of 35 μg L-IP-TK/GCV or GCV alone survived a median of 92 days and 68.7 days, respectively. There were no significant changes in glucose or insulin levels following treatment. In conclusion, multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity, suggesting non-viral vectors are superior to adenoviral vectors for IP-gene therapy. © 2015. Source

Ewing’s sarcoma is a devastating rare pediatric cancer of the bone. Intense chemotherapy temporarily controls disease in most patients at presentation but has limited effect in patients with progressive or recurrent disease. We previously described preliminary results of a novel immunotherapy, FANG (Vigil) vaccine, in which 12 advanced stage Ewing’s patients were safely treated and went on to achieve a predicted immune response (IFNγ ELISPOT). We describe follow-up through year 3 of a prospective, nonrandomized study comparing an expanded group of Vigil-treated advanced disease Ewing’s sarcoma patients (n = 16) with a contemporaneous group of Ewing’s sarcoma patients (n = 14) not treated with Vigil. Long-term follow-up results show a survival benefit without evidence of significant toxicity (no ≥ grade 3) to Vigil when administered once monthly by intradermal injection (1 × 10e6 cells/injection to 1 × 10e7 cells/injection). Specifically, we report a 1-year actual survival of 73% for Vigil-treated patients compared to 23% in those not treated with Vigil. In addition, there was a 17.2-month difference in overall survival (OS; Kaplan-Meier) between the Vigil (median OS 731 days) and no Vigil patient groups (median OS 207 days). In conclusion, these results supply the rational for further testing of Vigil in advanced stage Ewing’s sarcoma.Molecular Therapy (2016); doi:10.1038/mt.2016.86. © 2016 American Society of Gene & Cell Therapy Source

Phalon C.,Gradalis, Inc. | Rao D.D.,Gradalis, Inc. | Nemunaitis J.,Gradalis, Inc. | Nemunaitis J.,Mary Crowley Cancer Research Centers | Nemunaitis J.,Baylor Sammons Cancer Center
Expert Reviews in Molecular Medicine | Year: 2010

RNA interference (RNAi) is an evolutionary conserved mechanism for specific gene silencing. This mechanism has great potential for use in targeted cancer therapy. Understanding the RNAi mechanism has led to the development of several novel RNAi-based therapeutic approaches currently in the early phases of clinical trials. It remains difficult to effectively deliver the nucleic acids required in vivo to initiate RNAi, and intense effort is under way in developing effective and targeted systemic delivery systems for RNAi. Description of in vivo delivery systems is not the focus of this review. In this review, we cover the rationale for pursuing personalised cancer therapy with RNAi, briefly review the mechanism of each major RNAi therapeutic technique, summarise and sample recent results with animal models applying RNAi for cancer, and provide an update on current clinical trials with RNAi-based therapeutic agents for cancer therapy. RNAi-based cancer therapy is still in its infancy, and there are numerous obstacles and issues that need to be resolved before its application in personalised therapy focusing on patient-cancer-specific targets can become standard cancer treatment, either alone or in combination with other treatments. © Cambridge University Press 2010. Source

Shapiro G.I.,Dana-Farber Cancer Institute | Rodon J.,Sloan Kettering Cancer Center | Bedell C.,Mary Crowley Cancer Research Centers | Kwak E.L.,Massachusetts General Hospital | And 9 more authors.
Clinical Cancer Research | Year: 2014

Purpose: SAR245408 is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules [first 21 days of a 28-day period (21/7) and continuous once-daily dosing (CDD)], pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy. Experimental Design: Patients with refractory advanced solid malignancies were treated with SAR245408 using a 3 + 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair sheath cells, and skin and tumor biopsies. Results: Sixty-nine patients were enrolled. The MTD of both schedules was 600 mg; dose-limiting toxicities were maculopapular rash and hypersensitivity reaction. The most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite. Plasma pharmacokinetics showed a median time to maximum concentration of 8 to 22 hours, mean terminal elimination half-life of 70 to 88 hours, and 5- to 13-fold accumulation after daily dosing (first cycle). Steady-state concentration was reached between days 15 and 21, and exposure was dose-proportional with doses up to 400 mg. SAR245408 inhibited the PI3K pathway (∼40%-80% reduction in phosphorylation of AKT, PRAS40, 4EBP1, and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. A partial response was seen in one patient with advanced non-small cell lung cancer. Eight patients were progression-free at 6 months. Pharmacodynamic and clinical activity were observed irrespective of tumor PI3K pathway molecular alterations. Conclusions: SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600 mg administered orally with CDD. Clin Cancer Res; 20(1); 233-45. © 2013 AACR. Source

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