Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models

Feldmann, Georg; Mishra, Anjali; Bisht, Savita; Karikari, Collins; Garrido‐Laguna, Ignacio; Rasheed, Zeshaan A.; Ottenhof, Niki A.; Dadon, Tikva; Alvarez, Hector A.; Fendrich, Volker; Rajeshkumar, N. V.; Matsui, William; Brossart, Peter; Hidalgo, Manuel; Bannerji, Rajat; Maitra, Anirban; Nelkin, Barry D.

doi:10.4161/cbt.12.7.16475

Cited by 108 publications

(85 citation statements)

References 41 publications

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“…Subcutaneous murine xenografts of low-passage patient-derived human pancreatic cancers were generated as previously described (16,17,23). Six patient-derived xenograft models were chosen at random from the Johns Hopkins PDAC BioBank (23).…”

Section: Methodsmentioning

confidence: 99%

“…Three to eight weeks after subcutaneous implantation, mice for each case were randomized into four groups of five mice each, and assigned to receive treatment with vehicle control, dinaciclib, MK-2206, or dinaciclib + MK-2206. Total body weights were determined weekly, and xenograft tumor volumes were measured weekly using a digital caliper as previously described (17). After 3–5 weeks of treatment, mice were euthanized and tumor tissues harvested.…”

Section: Methodsmentioning

confidence: 99%

“…CDK5 knockdown, dominant negative expression or treatment with the CDK inhibitor dinaciclib (SCH727965; MK-7965) effectively inhibited RAS/RAL activation and resulted in substantial decreases in cell migration and anchorage independent growth in vitro, and of growth and metastasis of pancreatic cancer xenografts in vivo (16,17). Simultaneous blocking of CDK5 and the PI3K/AKT or RAF/MEK/ERK signaling pathways resulted in further inhibition of anchorage independent growth and cell migration (16).…”

Section: Introductionmentioning

confidence: 99%

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Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models

Dadon

Chenna

et al. 2015

Molecular Cancer Therapeutics

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KRAS is activated by mutation in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5), reduces pancreatic cancer growth and progression, through blockage of the centrally important RAL effector pathway, downstream of KRAS. In the current study, the therapeutic effects of combining the CDK inhibitor dinaciclib (SCH727965; MK-7965) with the pan-AKT inhibitor MK-2206 were evaluated using orthotopic and subcutaneous patient-derived human pancreatic cancer xenograft models. The combination of dinaciclib (20 mg/kg, i.p., t.i.w.) and MK-2206 (60 mg/kg, p.o., t.i.w.) dramatically blocked tumor growth and metastasis in all eight pancreatic cancer models examined. Remarkably, several complete responses were induced by the combination treatment of dinaciclib and MK-2206. The striking results obtained in these models demonstrate that the combination of dinaciclib with the pan-AKT inhibitor MK-2206 is promising for therapeutic evaluation in pancreatic cancer, and strongly suggest that blocking RAL in combination with other effector pathways downstream from KRAS may provide increased efficacy in pancreatic cancer. Based on these data, an NCI-CTEP approved multicenter Phase I clinical trial for pancreatic cancer of the combination of dinaciclib and MK-2206 (NCT01783171) has now been opened.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models

Dadon

Chenna

et al. 2015

Molecular Cancer Therapeutics

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“…Inhibiting CDK9 is known to cause minimal toxicity to normal cells (Lemke et al 2014, Li et al 2015. In vivo mouse xenograft models and phase I clinical trials have also shown that CDK9 inhibition results in minimal toxicity while maintaining effective antitumor activity (Abdullah et al 2011, Feldmann et al 2011, Nemunaitis et al 2013. Therefore, targeting CDK9 may offer safe and effective therapeutic strategy for patients afflicted with the advanced stages of PCa.…”

Section: :12mentioning

confidence: 99%

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman

Kumarasiri

Mekonnen

et al. 2016

Endocrine-Related Cancer

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Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and antiapoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.

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“…However, other important KRAS downstream effector signaling pathways have been more challenging to target therapeutically, the most prominent of these being the RalGEF-Ral (GEF = guanine nucleotide exchange factor) effector pathway [50]. It was recently shown that functional inhibition of cyclin-dependent kinase 5 (CDK5) is a way to indirectly block signaling through the RalGEF-Ral KRAS downstream effector axis [37,51]. Accordingly, inhibition of CDK5 function led to abrogation of the clonogenic potential of KRAS-mutant PDAC cells in vitro, which was mirrored by significantly delayed xenograft growth in nude mice [37].…”

Section: Novel Therapeutic Targetsmentioning

confidence: 99%

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

Feldmann¹

2018

Oncol Res Treat

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Pancreatic ductal adenocarcinoma (PDAC, pancreatic cancer) carries one of the poorest overall prognoses of all human malignancies known to date. Despite the introduction of novel therapeutic regimens, the outcome has not markedly improved over the past decades, the incidence rates are almost identical to the mortality rates, and PDAC is projected to soon become the second most common cause of cancer-related mortality in Western countries. Despite this clear medical need to develop novel therapeutic strategies against this dire malady, this need has so far not been addressed with sufficient institutional attention and support in terms of research funding and strategical programs. Given the still growing life expectancy and projected demographic changes with a growing proportion of senior citizens in many European societies, this discrepancy is likely to become even more pressing in the future. This article provides a brief overview of ongoing preclinical efforts to identify novel targets and, based on this, to develop novel strategies to treat advanced pancreatic cancer and improve survival and the quality of life of patients suffering from this malignancy.

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Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models

Cited by 108 publications

References 41 publications

Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models

Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

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