scholarly journals Molecular Approaches to Sarcoma Therapy

Sarcoma ◽  
2002 ◽  
Vol 6 (1) ◽  
pp. 27-42 ◽  
Author(s):  
R. J. Olsen ◽  
S. R. Tarantolo ◽  
S. H. Hinrichs
Keyword(s):  
Kinase Inhibitor ◽  
Clinical Success ◽  
Philadelphia Chromosome ◽  
Gene Mutations ◽  
Soft Tissue Sarcomas ◽  
Chimeric Protein ◽  
Chromosomal Translocation ◽  
Cellular Transformation ◽  
Molecular Approaches ◽  
Apoptotic Pathways

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed.

Nilotinib: A Review of its Use in Chronic Myelogenous Leukemia

2010 ◽  
Vol 2 ◽  
pp. CMT.S24
Author(s):  
Ting-Wei Lu ◽  
Ronan Swords ◽  
Francis J. Giles ◽  
Kevin Kelly
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Standard Of Care ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Large Randomized Control Trial ◽  
Prior Therapy ◽  
Frontline Treatment ◽  
Favourable Safety Profile

Chronic myeloid leukemia (CML) is characterized by the reciprocal chromosomal translocation, t(9;22), forming the BCR-ABL oncogene known as the Philadelphia chromosome. The development of imatinib, a small-molecule kinase inhibitor targeted against BCR-ABL, has revolutionized the management of CML and significantly improved the prognosis and outcome and until very recently was the standard of care in patients presenting with newly diagnosed CML. Nilotinib (Tasigna®) is an orally administered kinase inhibitor made by the Novartis Pharmaceuticals Corporation that was rationally designed to bind to the ABL kinase domain of BCR-ABL resulting in enhanced BCR-ABL inhibition. It is well tolerated and has a favourable safety profile. Nilotinib has been shown to be effective in patients who have failed prior therapy with imatinib. Recently a large randomized control trial comparing imatinib and nilotinib has demonstrated that niloitinb is superior to imatinib in the frontline treatment of CML. This review summarizes the preclinical and clinical data supporting the use of nilotinib in the frontline and secondline treatment of CML.

Design and stability of pediatric oral formulation of imatinib

2021 ◽  
pp. 107815522199120
Author(s):  
Mélanie Hinterlang ◽  
Amandine Gendron ◽  
Thomas Fleury ◽  
André Rieutord ◽  
Anastasia Vrana ◽  
...  
Keyword(s):  
High Performance ◽  
Protein Tyrosine Kinase ◽  
Pediatric Patients ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Oral Solution ◽  
Stability Study ◽  
Uv Detector ◽  
Stability Parameters ◽  
Tablet Dosage

Background Imatinib is a protein-tyrosine kinase inhibitor which is currently only commercially available as a tablet dosage form in the strength of 100mg and 400mg. The elaboration of new oral liquid formulations is suitable in pediatrics and for patients who have difficulties to swallow, notably in the absence of commercial forms. This enables the adaptation of dosage and secure the administration. Objectives The formulation of an oral pediatric solution of imatinib at a concentration of 30 mg/mL and the evaluation of its stability for the treatment of pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia. Methods The physicochemical stability parameters: appearance, pH, osmolality, and drug content of formulation were evaluated for 30 days when stored at 2–8°C. Concentration of solution was measured with a validated method using high performance liquid chromatography (HPLC) coupled with an absorbance UV detector. Equally, microbiological stability was performed. Results The remaining imatinib concentration was at least 95% of the initial concentration after 30 days stored in fridge temperature. No changes were observed regarding the physical properties of the formulation during the study period. Conclusions The stability study showed that the imatinib oral solution at a concentration of 30 mg/mL provides an alternative option at the commercial tablet dosage forms for pediatric patients and patients who have difficulties to swallow.

scholarly journals Potential Biomarkers for Treatment Response to the BCL-2 Inhibitor Venetoclax: State of the Art and Future Directions

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2974
Author(s):  
Haneen T. Salah ◽  
Courtney D. DiNardo ◽  
Marina Konopleva ◽  
Joseph D. Khoury
Keyword(s):  
Treatment Response ◽  
Gene Mutations ◽  
Hematologic Malignancies ◽  
Mechanisms Of Resistance ◽  
Apoptotic Pathway ◽  
Lymphoid Leukemia ◽  
Optimal Drug ◽  
Trisomy 12 ◽  
Apoptotic Pathways ◽  
Potential Biomarkers

Intrinsic apoptotic pathway dysregulation plays an essential role in all cancers, particularly hematologic malignancies. This role has led to the development of multiple therapeutic agents targeting this pathway. Venetoclax is a selective BCL-2 inhibitor that has been approved for the treatment of chronic lymphoid leukemia and acute myeloid leukemia. Given the reported resistance to venetoclax, understanding the mechanisms of resistance and the potential biomarkers of response is crucial to ensure optimal drug usage and improved patient outcomes. Mechanisms of resistance to venetoclax include alterations involving the BH3-binding groove, BCL2 gene mutations affecting venetoclax binding, and activation of alternative anti-apoptotic pathways. Moreover, various potential genetic biomarkers of venetoclax resistance have been proposed, including chromosome 17p deletion, trisomy 12, and TP53 loss or mutation. This manuscript provides an overview of biomarkers that could predict treatment response to venetoclax.

scholarly journals Characterization of the BCR promoter in Philadelphia chromosome-positive and -negative cell lines.

1991 ◽  
Vol 11 (4) ◽  
pp. 1854-1860 ◽  
Author(s):  
N P Shah ◽  
O N Witte ◽  
C T Denny
Keyword(s):  
Transcription Factor ◽  
Cell Lines ◽  
Transcription Initiation ◽  
Transcriptional Control ◽  
Philadelphia Chromosome ◽  
Gc Content ◽  
Cellular Transformation ◽  
Nucleotide Sequence Analysis ◽  
Coding Sequences ◽  
Gene Assay

The t(9;22) Philadelphia chromosome translocation fuses 5' regulatory and coding sequences of the BCR gene to the c-ABL proto-oncogene. This results in the formation of hybrid BCR-ABL mRNAs and proteins. The shift in ABL transcriptional control to the BCR promoter may play a role in cellular transformation mediated by this rearrangement. We have functionally localized the BCR promoter to a region 1 kb 5' of BCR exon 1 coding sequences by using a chloramphenicol acetyltransferase reporter gene assay. Nucleotide sequence analysis of this region revealed many consensus binding sequences for transcription factor SP1 as well as two potential CCAAT box binding factor sites and one putative helix-loop-helix transcription factor binding site. No TATA-like or "initiator" element sequences were found. Because of low steady-state levels of BCR mRNA and the high GC content (78%) of the promoter region, definitive mapping of transcription start sites required artificial amplification of BCR promoter-directed transcripts. Overexpression from the BCR promoter in a COS cell system was effective in demonstrating multiple transcription initiation sites. In order to assess the effects of chromosomal translocation on the transcriptional control of the BCR gene, we determined S1 nuclease protection patterns of poly(A)+ RNA from tumor cell lines. No differences were observed in the locations and levels of BCR transcription initiation sites between those lines that harbored the t(9;22) translocation and those that did not. This demonstrates that BCR promoter function remains intact in spite of genomic rearrangement. The BCR promoter is structurally similar to the ABL promoters. Together, this suggests that the structural fusion of BCR-ABL and not its transcriptional deregulation is primarily responsible for the transforming effect of the t(9;22) translocation.

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