An Orally Bioavailable and Highly Efficacious Inhibitor of CDK9/FLT3 for the Treatment of Acute Myeloid Leukemia.

Mutations in FMS-like tyrosine kinase 3 (FLT3) occur in approximately one-third of AML patients and are associated with a particularly poor prognosis. The most common mutation, FLT3-ITD, is a self-activating internal tandem duplication (ITD) in the FLT3 juxtamembrane domain. Many FLT3 inhibitors have shown encouraging results in clinical trials, but the rapid emergence of resistance has severely limited sustainable efficacy. Co-targeting of CDK9 and FLT3 is a promising two-pronged strategy to overcome resistance as the former plays a role in the transcription of cancer cell-survival genes. Most prominently, MCL-1 is known to be associated with AML tumorigenesis and drug resistance and can be down-regulated by CDK9 inhibition. We have developed CDDD11-8 as a potent CDK9 inhibitor co-targeting FLT3-ITD with Ki values of 8 and 13 nM, respectively. The kinome selectivity has been confirmed when the compound was tested in a panel of 369 human kinases. CDDD11-8 displayed antiproliferative activity against leukemia cell lines, and particularly potent effects were observed against MV4-11 and MOLM-13 cells, which are known to harbor the FLT3-ITD mutation and mixed lineage leukemia (MLL) fusion proteins. The mode of action was consistent with inhibition of CDK9 and FLT3-ITD. Most importantly, CDDD11-8 caused a robust tumor growth inhibition by oral administration in animal xenografts. At 125 mg/kg, CDDD11-8 induced tumor regression, and this was translated to an improved survival of animals. The study demonstrates the potential of CDDD11-8 towards the future development of a novel AML treatment.

CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents.

Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.

Validation of the Amharic Version of the Brief Fatigue Inventory for Assessment of Cancer-Related Fatigue in Ethiopian Cancer Patients.

BACKGROUND: Although cancer-related fatigue (CRF) is a highly prevalent and distressing symptom associated with cancer and its treatment, it is mostly underscreened, underassessed, and undertreated. The Brief Fatigue Inventory (BFI) is a reliable and valid instrument to assess CRF. OBJECTIVE: To validate the Amharic version of the BFI (BFI-Am) for assessment of CRF in Ethiopian cancer patients. METHODS: The BFI-Am was developed from its original English version through standard forward-backward translation approach. Two hundred eight consented cancer patients filled the questionnaires, along with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, version 3. In addition, sociodemographic and clinical information were collected. Psychometric properties of the BFI-Am were evaluated in terms of acceptability, internal consistency, construct validity, concurrent validity, and known group validity. Linear regression analysis was performed to identify possible predictors of fatigue severity. RESULTS: Two hundred two cancer patients completed the questionnaires and included in the data analysis. The BFI-Am had an overall Cronbach's alpha of 0.97. The results of the principal axis factor analysis suggested a one-factor solution explaining 78.4% of the variance, supporting the hypothesis of unidimensionality of the BFI-Am. The global BFI-Am interference items score was highly correlated with fatigue subscale score of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 than single items, showing an inverse correlation between the BFI-Am and the global health status/quality of life (r = -0.324; P = 0.000). The BFI-Am significantly detected the differences in fatigue severity in patients with poor performance status (P < 0.001), indicating known group validity. CONCLUSION: The BFI-Am is an excellent assessment tool with adequate psychometric properties for use in both clinical management and symptom research of CRF in Ethiopian cancer patients.

Validation of the Amharic Version of the Brief Pain Inventory for Utility in Ethiopian Cancer Patients.

BACKGROUND: Pain is a highly prevalent and distressing symptom in patients with cancer but at the same time inadequately treated in many of these patients. The major reason for such imbalance is inappropriate pain assessment. To overcome such a barrier, the use of a valid and reliable pain assessment tool in the language the patient understands is invaluable. Unfortunately, until now, no such standardized tool has been utilized in Ethiopian patients with cancer for both clinical and research purposes. OBJECTIVES: This study tried to validate the Amharic language version of the Brief Pain Inventory (BPI-Am) and evaluate the adequacy of cancer pain management using the Pain Management Index (PMI). METHODS: A standard forward/backward translation technique was used for translating the BPI from its original English version into Amharic (BPI-Am). The BPI-Am was administered to 291 Ethiopian patients with cancer who fulfilled the inclusion criteria. Factor analysis was used to identify the underlying constructs of the tool. Mean comparison was used to confirm the sensitivity of the BPI-Am to known patient groups that differed based on their performance status. Cronbach's α and intraclass correlation coefficients, respectively, were used to assure internal consistency and test-retest reliability of the BPI-Am. The PMI was calculated to identify the level of inadequate pain management in the current sample. Stepwise logistic regression was used to identify potential predictors of inadequate pain management. RESULTS: Factor analysis yielded 3 factors-pain severity, physical activity interference, and psychosocial interference-with Cronbach's α coefficients of 0.85, 0.87, and 0.77, respectively. The BPI-Am showed the capacity to detect higher mean pain severity and mean pain interference scores in patients with poor performance status as compared with those having a good performance status (P < 0.001). Intraclass correlation coefficients for test-retest reliability were 0.75 and 0.78 for the pain severity and pain interference composite scores, respectively. Sixty-seven percent of patients in the current sample were inadequately treated for their pain according to the PMI. Good performance status (odds ratio [OR] = 2.9, P < 0.01), absence of cancer-related complications (OR = 2.1, P < 0.05), and being unemployed (OR = 2.6, P < 0.01) were identified as predictors of inadequate pain management. CONCLUSION: The BPI-Am is a valid and reliable tool for use in Ethiopian patients with cancer. The inadequacy of cancer pain management in these groups of patients is high, which calls for needed attention.

Validation of the Amharic Version of the M. D. Anderson Symptom Inventory and Assessment of Symptoms in Ethiopian Cancer Patients.

CONTEXT: Cancer patients often face a variety of symptoms that impact their quality of life. The management of these symptoms is highly dependent on the accurate appraisal of their severity through the use of a standardized symptom assessment tool. The M. D. Anderson Symptom Inventory (MDASI), developed in English, is one of such tools that contain 13 core cancer related symptoms that can easily be rated on a scale of 0-10. OBJECTIVES: The present study tried to develop and validate the Amharic language version of the MDASI (MDASI-Am). METHODS: The MDASI-Am was developed by the standard forward/backward translation of the original English version of the MDASI. The MDASI-Am was completed by or administered to 145 randomly selected Ethiopian cancer patients. Factor analysis, Cronbach α coefficient, and mean comparison, respectively, were used to establish construct validity, internal consistency, and known-group validity (Eastern Cooperative Oncology Group Performance Status). RESULTS: Factor analysis identified three symptom constructs interpreted as general, gastrointestinal, and neuropsychiatric symptoms, with Cronbach α coefficients of 0.70, 0.80, and 0.82, respectively. The MDASI-Am significantly detected differences in symptom severity and interference levels in patient groups categorized according to Eastern Cooperative Oncology Group Performance Status (P < 0.01), establishing known-group validity. The most prevalent severe symptoms identified in the current sample were pain, sadness, numbness, distress, and fatigue. CONCLUSION: The MDASI-Am is a valid and reliable tool for measuring symptom severity and symptom interference with daily living in Ethiopian cancer patients.