The interest of our lab is to identify and understand mechanisms of damage survival. People who inherit a deficiency in damage response are predisposed to develop cancer, usually as children or young adolescents. Further, most cancer treatments are based on damaging cancer cells, so understanding why a chemotherapy works, and for which patients, should lead to more effective and less toxic treatments that will increase the cure rate and improve quality of life for cancer survivors.
Traveling the road of childhood cancer, from cause to cure...
Ewing sarcoma– a bone/tissue sarcoma
Ewing sarcoma usually displays exquisite sensitivity to a variety of damaging agents (chemotherapies), but the reason for this damage response defect is not known. Our work identified that these sarcomas lack most of the normal damage responses because of an RNA metabolism issue that traps the BRCA1 protein, the gene usually associated with breast cancer. The unavailability of BRCA1 leads to a DNA repair defect that can be specifically targeted in the treatment of these cancers.
Ataxia telangiectasia –
Ataxia telangiectasia (AT) is caused by a mutation in ATM, a key damage response gene. AT patients suffer from immune dysfunction, neurological defects, as well as a cancer and diabetes predisposition. Aside from understanding that AT cells are sensitive to irradiation, little is understood about the clinical manifestation of the disease. To develop new insights we have examined the diabetes development associated with this disease and discovered that ß-cells have a metabolic problem resulting from a defect in importing cysteine; this defect results in an accumulation of glutamate and a defect in respiration. These observations provide new insight into disease development. Further, we have been able to demonstrate that we can rescue the diabetes phenotype by circumventing the cysteine import defect. We are now exploring the impact of this defect and intervention on the neurological defect and cancer development in AT.
Homologous recombination defective diseases
Homologous recombination defective diseases combination is associated with BRCA1 and BRCA2, the breast and ovarian cancer predisposing genes. We are particularly interested in mechanisms that control homologous recombination. Towards this we study proteins such as BLM, p53, 53BP1, ATR and CREBBP. When the genes of these proteins are inherited in a mutated for they lead to diseases usually associated with early onset cancer; Bloom syndrome, Li Fraumeni, Seckel syndrome and Myelodysplastic syndrome. Using mouse and cell models we work to examine these diseases, their impact on homologous recombination and the molecular basis of these interactions. We have already discovered new roles for some of these proteins. For example, 53BP1 mutation occurs in chemorefractory BRCA1 breast cancers and Ewing’s sarcoma. However, we have found that loss of 53BP1 also results in DNA replication stress and this provides a new avenue for treating those cancers that have acquired these mutations. It is exactly this type of novel insight that expect will lead to better, more targeted therapies and preventative measures. Because of the interactions with homologous recombination and BRCA1/BRCA2 proteins our work also impacts adult cancers, particularly breast and ovarian cancers. More importantly, because of the these relationships, we hope to take advantage of the discoveries for targeted therapies developed in adult cancers to apply to childhood cancers.
Alex Bishop, D.Phil., joined the Greehey Children’s Cancer Research Institute in September of 2004 with major faculty responsibilities as a Principal Investigator in Molecular Oncogenesis. He is also an Associate Professor in the Department of Cellular and Structural Biology and a member of both the Cancer Therapy and Research Center (a NCI-designated cancer center). He received his doctoral degree from Oxford University and completed two post-doctoral fellowships at Harvard University.
Dr. Bishop is a molecular geneticist whose research focuses on DNA damage responses and the resultant genomic instability, a fundamental cause of cancer. His laboratory is involved in two major lines of research, discovering new genes and pathways involved in damage survival and understanding how damage survival genes affect maintenance of genomic integrity via the homologous recombination process. The goal is to apply the knowledge gained to the treatment of cancer. This work has several important applications, including improving our understanding of the basic biology of cellular processes, providing insights into cancer etiology and progression and identifying prognostics for cancer treatment as well as developing novel treatment strategies.
Homologous Recombination Repair - DNA repair by homologous recombination
Systems biology - RNAi screening, protein interactome and comparative biology
Funding Agency NIH NCI
Title Improving etoposide treatment of Ewing's sarcoma
Status Active Active
Role Principal Investigator
Grant Detail To identify genes involved in surviving etoposide exposure and to determine the utility of targeting these genes to improve etoposide treatment of Ewings sarcoma.
Funding Agency Cancer Prevention & Research Institute of Texas
Title Ewing's sarcoma, a homologous recombination defective disease
Status Active Active
Role Principal Investigator
2010 - Cellular and Structural Biology Award for Excellence in
Graduate Student Education:
- Award for teaching contributions to the Department.
2010 - Voelcker Fund Young Investigator Award
2009 - NCI Travel Award: Award to attend and present at the 3rd US-EU workshop Systems Biology of the DNA Damage Response
2004 - K22 Transitions to Independent Positions: Fellowship from NIEHS (NIH).
2002 - Keystone Scholarship: Scholarship to Replication and Recombination Conference
2001 - Keystone Scholarship:Scholarship to Molecular Basis of Cancer Conference
1999 - ASM Travel Grant: Award to attend ASM DNA repair meeting
1999 - Keystone Scholarship: Scholarship to attend Molecular Basis of Cancer Conference
1997 - F32 Postdoctoral Fellowship: Fellowship from NIGMS (NIH)
1997 - ACS Postdoctoral Fellowship (not accepted due to F32 Fellowship award)
1993 - MRC (UK) Graduate Student Fellowship: Fellowship for PhD studies