Use of Microdialysis in Preclinical and Clinical Development of Anticancer Agents

2004 ◽  
pp. 307-326
Author(s):  
William C. Zamboni
Keyword(s):  
Anticancer Agents ◽  
Clinical Development

In vivo platform for translational drug development and biomarker discovery in pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4000-4000 ◽  
Author(s):  
M. Hidalgo ◽  
B. Rubio-Viqueira ◽  
C. Weekes ◽  
D. Song ◽  
P. Shah ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Anticancer Agents ◽  
Biomarker Discovery ◽  
Pancreas Cancer ◽  
Ex Vivo ◽  
Single Agent ◽  
Clinical Development ◽  
Genetic Features ◽  
Gene Status

4000 While there are many new agents entering clinical development, there is very little data to prioritize which agents should be explored in pancreas cancer. Furthermore, often there is no information on biomarkers that may predict the activity of these drugs in pancreas cancer. In this project, we have generated a cohort of 30 pancreatic cancer xenografts by implanting in nude mice tumor materials from surgical specimens. Molecular studies show that a) these tumors maintain the genetic features of the originator cancer such as KRAS, p53 and DPC4 gene status; b) tumors represent the heterogeneity of pancreatic cancer well (there is not selection of any genotype in the xenograft ) and c) features do not changed over time. We have used this platform to explore the activity of a battery with a total of 10 new anticancer agents including inhibitors of MAPK, EGFR, mTOR, src kinase, Ras oncogene, mitosis regulators, angiogenesis, heat shock protein and hedgehog pathway inhibitors using a methodology similar to a two stage phase II clinical trial. All agents are tested against 10 xenografts. Those inactive are not explored anymore. Active agents are tested against the full set of tumors. Thus far we have shown that inhibitors of mTOR and MAPK have substantial activity in this model while Ras interacting agents and EGFR targeted drugs have no single agent activity. For active agents, we have characterized the tumors for potential strategies and biormarkers that may predict activity using both a target-focus approach as well as general profiling approach. Signaling inhibitors are more active in tumors with evidence of activation of the targeted pathway. In addition, ex vivo assays indicate that the ability to inhibit the targeted pathway is associated with agent activity. This information may help to prioritize agents for clinical development in pancreatic cancer. [Table: see text]

scholarly journals Purine nucleoside analogs in the therapy of cancer and neuroinflammation

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Danijela Savić ◽  
Tijana Stanković ◽  
Irena Lavrnja ◽  
Ana Podolski-Renić ◽  
Jasna Banković ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Drug Administration ◽  
Anticancer Agents ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Clinical Development ◽  
Purine Nucleoside ◽  
Clinical Use ◽  
The Past ◽  
Pathological Conditions

Abstract:Purine nucleoside analogs have been in clinical use for almost 50 years. At the beginning developed as antiviral agents, later their efficacy was demonstrated in cancer treatment, especially hematological malignances. The approval of new purine nucleoside analogs by US Food and Drug Administration (FDA) over the past decade implies that the interest for these drugs still exists. Here, we review new nucleoside analogs that are currently in preclinical or clinical development as anticancer agents. In addition, we highlight the potential for implementation of these drugs in other pathological conditions, particularly in neuroinflammation.

Novel anticancer agents in early clinical development

2002 ◽  
Vol &NA; (1339) ◽  
pp. 9-11
Author(s):  
Rachael Pepperle ◽  
Raewyn Poole
Keyword(s):  
Anticancer Agents ◽  
Clinical Development ◽  
Early Clinical Development

scholarly journals Novel Anticancer Agents in Clinical Development

2003 ◽  
Vol 2 (sup1) ◽  
pp. 4-14 ◽  
Author(s):  
Alex A. Adjei ◽  
Eric K. Rowinsky
Keyword(s):  
Anticancer Agents ◽  
Clinical Development

CLINICAL DEVELOPMENT OF HISTONE DEACETYLASE INHIBITORS AS ANTICANCER AGENTS

2005 ◽  
Vol 45 (1) ◽  
pp. 495-528 ◽  
Author(s):  
Daryl C. Drummond ◽  
Charles O. Noble ◽  
Dmitri B. Kirpotin ◽  
Zexiong Guo ◽  
Gary K. Scott ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Clinical Development ◽  
Clinical Activity ◽  
Innovative Drug ◽  
Nonhistone Proteins ◽  
Drug Classes

Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.

scholarly journals Advances of Benzimidazole Derivatives as Anticancer Agents: Bench to Bedside

2022 ◽  
Author(s):  
Kashif Haider ◽  
Mohammad Shahar Yar
Keyword(s):  
Cancer Research ◽  
Biological Activity ◽  
Anticancer Drugs ◽  
Broad Spectrum ◽  
Anticancer Agents ◽  
Therapeutic Potential ◽  
Structural Features ◽  
Clinical Development ◽  
Benzimidazole Derivatives ◽  
Antimitotic Agent

Benzimidazole is one of the privileged nitrogen-containing scaffolds known for its versatile diversified role in insecticides, pesticides, dyes, pigments and pharmaceuticals. Due to its electron-rich environment, structural features and binding potency of various therapeutic targets, benzimidazole derivatives exhibit a broad spectrum of biological activity that majorly includes antimicrobial, antifungal, analgesics, anti-diabetic and anticancer agents. Several benzimidazole scaffolds bearing drugs are clinically approved; they are used for various indications. For example, Bilastine, Lerisetron, Maribavir and Nocodazole are the most widely used benzimidazole-based marketed drugs available as an antihistamine, antiviral and antimitotic agent, respectively. Another example is the recently approved anticancer drug Binimetinib and Selumetinib, which are indicated for BRAF mutated melanoma and plexiform neurofibromas. Not only this, many benzimidazole-based anticancer drugs are in late phases of clinical development. Due to the vast therapeutic potential of benzimidazole scaffold in cancer research, medicinal chemists have gained a lot of attraction to explore it more and develop novel, highly effective and target-specific benzimidazole-based potential anticancer drugs.

scholarly journals Novel therapies emerging in oncology to target the TGF-β pathway

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Byung-Gyu Kim ◽  
Ehsan Malek ◽  
Sung Hee Choi ◽  
James J. Ignatz-Hoover ◽  
James J. Driscoll
Keyword(s):  
Small Molecule ◽  
Anticancer Agents ◽  
Kinase Inhibitor ◽  
Clinical Development ◽  
Response To Therapy ◽  
Tumor Promoter ◽  
Multiple Drug ◽  
Tumor Escape ◽  
Dependent Manner ◽  
Patient Responses

AbstractThe TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.

Clinical development of anticancer agents from natural products

Stem Cells ◽  
1994 ◽  
Vol 12 (1) ◽  
pp. 30-43 ◽  
Author(s):  
David R. Parkinson ◽  
Susan G. Arbuck ◽  
Timothy Moore ◽  
James M. Pluda ◽  
Michaele C. Christian
Keyword(s):  
Natural Products ◽  
Anticancer Agents ◽  
Clinical Development
Sign in / Sign up

Export Citation Format

Share Document