A phase I safety and dose escalation trial of docetaxel combined with GEM®231, a second generation antisense oligonucleotide targeting protein kinase A R1α in patients with advanced solid cancers

Goel, Sanjay; Desai, Kavita; Macapinlac, M. P.; Wadler, Scott; Goldberg, Gary L.; Fields, Abbie L.; Einstein, Mark H.; Volterra, Fabio; Wong, Benny; Martin, Russell; Mani, Sridhar

doi:10.1007/s10637-006-2378-x

Cited by 29 publications

(8 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The antisense oligonucleotide GEM231 has been evaluated in two phase I clinical trials (Table 2 ). The results of the phase I clinical trial of GEM231 in combination with docetaxel showed that the overall incidence of grade 3 adverse reactions, including fatigue, elevated aminotransferase, neutropenia and altered mental status, was 75% in 20 patients with refractory solid tumors during 39 cycles of treatment [ 144 ]. No subsequent clinical trial has been reported.…”

Section: Targeting Camp–pka Pathway For Cancer Therapymentioning

confidence: 99%

Complex roles of cAMP–PKA–CREB signaling in cancer

et al. 2020

View full text Add to dashboard Cite

Cyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP–PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP–PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP–PKA–CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.

show abstract

Section: Targeting Camp–pka Pathway For Cancer Therapymentioning

confidence: 99%

Complex roles of cAMP–PKA–CREB signaling in cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In fact, in a nude mouse model of human prostate, colon, lung and pancreas cancer cells’ xenotransplantation, simultaneous GEM231 administration determined enhanced irinotecan antitumor activity (68). In a Phase I study on 20 patients with different solid tumors, GEM231 (220 mg/m 2 , twice a week) was administered and coupled with a variable dose of Docetaxel [ 79 ]. Liver toxicity was frequently observed (increase of transaminases levels in 75% of patients) as well as neutropenia (45%) and fatigue (40%).…”

Section: Camp and Cancermentioning

confidence: 99%

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

Baiocchi

Lenci

Mihalj

et al. 2021

Cells

View full text Add to dashboard Cite

Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes’ injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes’ proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.

show abstract

“…A slight elevation of transaminases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was noted, although the levels were still within normal range. Similarly, Phase I and II clinical trials of mipomersen, a phosphorothioate antisense oligonucleotide for apolipoprotein B synthesis inhibitor, showed transient dose-dependent elevation of AST and ALT over 5-week treatment (30–400 mg/week) [ 75 , 76 ]. In a randomized, placebo-controlled, dose-escalation Phase II study of mipomersen for 5–13-week treatment, an increase of ALT was noted among 17% of patients (10 of 59 cases), to a level more than three times the upper limit of the normal range [ 76 ].…”

Section: Challenges and Possible Solutions In Aptamer Therapeuticsmentioning

confidence: 99%

Aptamer Therapeutics in Cancer: Current and Future

Morita

Leslie

Kameyama

et al. 2018

Cancers

164

112

View full text Add to dashboard Cite

Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small—approximately one-tenth that of monoclonal antibodies—their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesized and modified. In addition, aptamers’ long storage period and low immunogenicity are favorable properties for clinical utility. Due to their flexibility of chemical modification, aptamers are conjugated to other chemical entities including chemotherapeutic agents, siRNA, nanoparticles, and solid phase surfaces for therapeutic and diagnostic applications. However, as relatively small sized oligonucleotides, aptamers present several challenges for successful clinical translation. Their short plasma half-lives due to nuclease degradation and rapid renal excretion necessitate further structural modification of aptamers for clinical application. Since the US Food and Drug Administration (FDA) approval of the first aptamer drug, Macugen® (pegaptanib), which treats wet-age-related macular degeneration, several aptamer therapeutics for oncology have followed and shown promise in pre-clinical models as well as clinical trials. This review discusses the advantages and challenges of aptamers and introduces therapeutic aptamers under investigation and in clinical trials for cancer treatments.

show abstract

A phase I safety and dose escalation trial of docetaxel combined with GEM®231, a second generation antisense oligonucleotide targeting protein kinase A R1α in patients with advanced solid cancers

Abstract: The recommended dose for further development of the combination of docetaxel and GEM231 is 75 mg/m2 and 220 mg/m2, respectively. It is important to administer GEM231 twice weekly for 2 consecutive weeks followed by a one-week break.

Cited by 29 publications

References 35 publications

Complex roles of cAMP–PKA–CREB signaling in cancer

Complex roles of cAMP–PKA–CREB signaling in cancer

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

Aptamer Therapeutics in Cancer: Current and Future

Contact Info

Product

Resources

About