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Biomedical subjects

Dean W Felsher

Publications and source records attributed to Dean W Felsher.

27 records · Page 2Linked to original sources
PubMed2004

Reversibility of oncogene-induced cancer.

Cancer can largely be conceived as a consequence of genomic catastrophes resulting in genetic events that usurp physiologic function of a normal cell. These genetic events mediate their pathologic effects by either activating oncogenes or inactivating tumor-suppressor genes. The targeted repair or inactivation of these damaged gene products may counteract the effects of these genetic events, reversing tumorigenesis and thereby serve as an effective therapy for cancer. However, because they are the result of many genetic events, the inactivation of no single mutant gene product may be sufficient to reverse cancer. Despite this caveat, compelling recent evidence suggests that there are circumstances when even the brief interruption of activation of a single oncogene can be sufficient to reverse tumorigenesis. Understanding how and when oncogene inactivation reverses cancer will be important in both defining the molecular pathogenesis of cancer as well as developing new molecularly based treatments.

DNA Repair↗
PubMed2004

Conditional animal models: a strategy to define when oncogenes will be effective targets to treat cancer.

The ability to model cancer in the mouse has provided a robust methodology to dissect the molecular etiology of cancer. These models serve as potentially powerful platforms to preclinically evaluate novel therapeutics. In particular, the recent development of strategies to conditionally induce the or knockout the function of genes in a tissue specific manner has enabled investigators to engineer mice to demonstrate that the targeted inactivation of specific oncogenes can be effective in inducing sustained regression of tumors. Thus, these animal models will be useful to define the specific genes that will be therapeutically useful to target for the treatment of particular human cancers.

Animals↗
PubMed2003

Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression.

DNA repair mechanisms are essential for the maintenance of genomic integrity. Disruption of gene products responsible for DNA repair can result in chromosomal damage. Improperly repaired chromosomal damage can result in the loss of chromosomes or the generation of chromosomal deletions or translocations, which can lead to tumorigenesis. The MYC protooncogene is a transcription factor whose overexpression is frequently associated with human neoplasia. MYC has not been previously implicated in a role in DNA repair. Here we report that the overexpression of MYC disrupts the repair of double-strand DNA breaks, resulting in a several-magnitude increase in chromosomal breaks and translocations. We found that MYC inhibited the repair of gamma irradiation DNA breaks in normal human cells and blocked the repair of a single double-strand break engineered to occur in an immortal cell line. By spectral karyotypic analysis, we found that MYC even within one cell division cycle resulted in a several-magnitude increase in the frequency of chromosomal breaks and translocations in normal human cells. Hence, MYC overexpression may be a previously undescribed example of a dominant mutator that may fuel tumorigenesis by inducing chromosomal damage.

Base Sequence↗
PubMed2003

Cancer revoked: oncogenes as therapeutic targets.

Recent findings show that even the brief inactivation of a single oncogene might be sufficient to result in the sustained loss of a neoplastic phenotype. It is therefore possible that the targeted inactivation of oncogenes could be a specific and effective treatment for cancer. So why does oncogene inactivation cause tumour regression and will this be a generally successful approach for the treatment of human neoplasia?

Animals↗
PubMed2002

Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations.

The targeted inactivation of oncogenes may be a specific and effective treatment for cancer. However, because human cancers are the consequence of multiple genetic changes, the inactivation of one oncogene may not be sufficient to cause sustained tumor regression. Moreover, cancers are genomically unstable and may readily compensate for the inactivation of a single oncogene. Here we confirm by spectral karyotypic analysis that MYC-induced hematopoietic tumors are highly genetically complex and genomically unstable. Nevertheless, the inactivation of MYC alone was found to be sufficient to induce sustained tumor regression. After prolonged MYC inactivation, some tumors exhibited a distinct propensity to relapse. When tumors relapsed, they no longer required the overexpression of MYC but instead acquired novel chromosomal translocations. We conclude that even highly genetically complex cancers are reversible on the inactivation of MYC, unless they acquire novel genetic alterations that can sustain a neoplastic phenotype.

Animals↗
PubMed2002

Sustained loss of a neoplastic phenotype by brief inactivation of MYC.

Pharmacological inactivation of oncogenes is being investigated as a possible therapeutic strategy for cancer. One potential drawback is that cessation of such therapy may allow reactivation of the oncogene and tumor regrowth. We used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. These results raise the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.

Animals↗
PubMedDate not supplied

Pharmacological inactivation of MYC for the treatment of cancer.

The overexpression of the MYC proto-oncogene has been implicated in the pathogenesis of most types of human cancer. Recent experimental observations indicate that the inactivation of MYC may be effective in the treatment of neoplasia. Several different strategies have been employed to develop novel drugs that may be effective to target the inactivation of MYC for the treatment of cancer. Some of these strategies are discussed.

Animals↗
PubMedDate not supplied

How cancers escape their oncogene habit.

Many recent reports demonstrate that at least initially, the inactivation of an oncogene can induce sustained regression of even a highly invasive and genetically complex cancer. However, upon prolonged oncogene inactivation, some cancers ultimately relapse, becoming independent of the very oncogene that initiated the process of tumorigenesis. Understanding the specific mechanisms by which cancers can escape dependence upon a particular oncogene will be critical to anticipate mechanisms by which human cancers will evade therapies that target individual oncogenes. Thereby, more effective strategies will be developed to clinically treat cancer.

Animals↗