Overview of Molecular Pathways in Melanoma
Sanjiv S. Agarwala, Vernon K. Sondak in Melanoma, 2008
While unable to therapeutically replace deleted tumor-suppressor proteins, there are other ways of mechanistically repairing and/or restoring cell cycle regulation. Varied drugs that function as CDK inhibitors are being investigated and include older agents, such as flavopiridol (alvocidib, Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey, U.S.), as well as newer selective inhibitors that target one or several CDKs (103,104). The therapeutic goal of CDK inhibitors is to effect cell cycle arrest in lieu of aberrant regulatory controls, facilitating apoptotic tumor cell death (103). In metastatic melanoma, flavopiridol, a pan-CDK inhibitor, demonstrated stable disease in 7 of 16 patients treated but no objective responses (105). Novel small-molecule inhibitors, all under phase I investigation, include: PD-0332991 (Pfizer) which inhibits CDK 4/6 (106), SNS-032 (BMS-387032, Sunesis, South San Francisco, California, U.S.) which inhibits CDK 2/7/9, and ZK 304709 (Schering AG, Berlin, Germany) which inhibits CDK 1/2/4/7/9 as well as VEGFR 1/2/3 and PDGFR-β (107,108). Therapeutic agents aimed at epigenetic alterations as well as at the proteasome may be relevant in tumors with aberrant cell cycle controls.
Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Transcription factors are proteins that control the DNA transcriptional process by selectively binding to a target sequence in the promoter region of the relevant gene to stimulate or inhibit transcription. They work by modifying the activity of RNA Polymerase II (Pol II) to ensure that transcription occurs (or not) at the appropriate time and place in the genome. Cancer therapies based on inhibiting the transcription of oncogenes such as C-Myc, HIF-1, NFκB, and STAT-3 have been envisaged. A number of small molecules inhibitors have been reported such as alvocidib, echinomycin, PBD molecules (e.g., TSG-1301), and the hairpin polyamides that can bind to duplex DNA in a sequence-selective manner and inhibit transcription. Some of these molecules are described in Section 5.7.1.1.1, although none have reached the approval stage.
Chemistry and Pharmacology of Naturally Occurring Flavoalkaloids
Namrita Lall in Medicinal Plants for Cosmetics, Health and Diseases, 2022
The flavoalkaloids have a unique structure consisting of phenols and a basic nitrogen atom resulting from the convergence of specific biosynthetic pathways. Though these compounds are difficult to extract, they possess various biological properties, which cannot be obtained from flavonoids and alkaloids alone. One such example is flavopiridol (known as alvocidib), a semisynthetic flavoalkaloid that is used currently under clinical investigation as a potential CDK 9 kinase inhibitor for the treatment of various cancers (Senderowicz et al., 1999). Flavopiridol showed promising results in the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and will undergo stage III clinical trials in due time (Zeidner et al., 2015).
Apoptosis targeted therapies in acute myeloid leukemia: an update
Published in Expert Review of Hematology, 2020
Somedeb Ball, Gautam Borthakur
To counter the potential development of resistance to BCL inhibitor, several combination strategies have been explored to restore the sensitivity of AML cells to venetoclax. Addition of Janus kinase (JAK)-2 inhibitor ruxolitinib helped AML cells overcome venetoclax resistance mediated by bone marrow stromal cells through downregulation of BCL-XL and/or MCL1 [43,44]. Cyclin-dependent kinase inhibitor alvocidib modulates the balance of BCL2 family proteins through decreased Mcl-1 and/or increased pro-apoptotic proteins such as BIM or NOXA, to favor apoptosis of AML cells [45]. Combination of venetoclax with other kinase inhibitors such as Bruton tyrosine kinase inhibitor (ibrutinib) or phosphatidylinositol 3-kinase inhibitor has shown promising activity in preclinical models [46,47]. Relevant to recent clinical developments, the addition of 5-azacytidine (AZA) was shown to potentiate venetoclax-induced apoptosis through transcriptional activation of pro-apoptotic protein NOXA [48]. The deep and durable response noted in clinical studies with this combination (venetoclax plus AZA) could be secondary to the inhibition of electron transport chain complex II and resultant disruption of oxidative phosphorylation in leukemic stem cells. This metabolic effect was thought to be mediated through a reduced level of glutathione, and was not reproducible with venetoclax alone [49]. The use of AZA and pan-BCL2 inhibitor ABT-737 synergistically induced apoptosis in AML cells independent of p53 expression, through significant downregulation of MCL1 [50].
Precision medicine in acute myeloid leukemia: where are we now and what does the future hold?
Published in Expert Review of Hematology, 2020
Juan Eduardo Megías-Vericat, David Martínez-Cuadrón, Antonio Solana-Altabella, Pau Montesinos
Functional tests using predictive biomarkers of response are being tested, as for cyclin-dependent kinase (CDK)9 inhibitors. Alvocidib downregulates the transcription of myeloid cell leukemia-1 (MCL-1) gene, an antiapoptotic protein responsible in promoting cell survival of blast. Sensitivity to alvocidib is being investigated with BCL-2 homology domain 3 (BH3) profiling. This biomarker is based on mitochondrial depolarization following exposure to the peptide NOXA-BH3 when interacts with MCL-1, suggesting that the AML samples that are most responsive to alvocidib plus cytarabine and mitoxantrone (FLAM) are highly dependent on MCL-1 for survival [52]. Ongoing clinical trials included as eligibility criteria ≥40% myeloblast MCL-1 dependency determined by BH3 profiling in phase II trial in R/R AML (NCT02520011) [53] and in a phase I in untreated AML (NCT03298984).
An overview of novel therapies in advanced clinical testing for acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Sangeetha Venugopal, Zhuoer Xie, Amer M. Zeidan
In the phase 1 trial of alvocidib, a potent, nonselective CDK-9 inhibitor in combination with ‘7 + 3’ chemotherapy in patients with newly diagnosed AML and non-favorable cytogenetics, was administered on days 1–3 prior to starting 7 + 3 [76]. There was no dose-limiting toxicity, and maximal tolerated dose of alvocidib was not reached. The most common grade ≥3 TEAE included diarrhea (44%) and tumor lysis syndrome (34%) which did not warrant treatment discontinuation. Alvocidib in combination with 7 + 3 demonstrated clinical activity with a CR rate of 65%. Of note, there was no correlation between MCL-1 dependence and treatment response in this cohort, although the analysis was limited by small numbers. However, further development of alvocidib was halted in May 2021 due to sponsor decision. Several other CDK 9 inhibitors such as AZD4573, CYC065 are in early phase clinical development.
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