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P450-armed Replication-Specific/Adaptive Adenovirus for Chemo-resistant Breast Cancer Treatment
Background: Several cancer-specific characteristics can be used to achieve tumor-specific viral replication and oncolysis. These traits are: overexpression of DF3-MUC1 antigen, telomerase activation and defects in p53 tumor suppressor gene. However, these defects are only partially overlapping, and can be heterogeneous within a given tumor, and its metastases, thus reducing the effectiveness of oncolytic viruses.
Objective/Hypothesis: I hypothesize that oncolytic viruses whose replication integrates three common cancer traits are more likely to eliminate breast cancer in a large population of breast cancer patients, as well as in a patient presenting several breast cancer defects. I further hypothesize that this virus will be more able at eliminating breast cancer cells if armed with a highly efficient cyclophosphamide (CPA)-activating P450 enzyme, CYP2B11.
Specific Aims: I propose to construct a replication-specific conditional adenovirus that will replicate in breast cancer cells that are p53-deficient, overexpress DF3-MUC1 antigen, or express telomerase (hTERT), thus replicating and destroying a wide spectrum of breast cancer malignancies. Aim 1 is to generate and evaluate in vitro an E1B-deleted, DF3-MUC1-E1A- and hTERT-E1A-regulated breast cancer replication-specific adenovirus; Aim 2 is to generate a P450-armed breast cancer replication-specific adenovirus; and Aim 3 is to evaluate the P450-armed, breast cancer replication-specific adenovirus for breast cancer treatment in animal models.
Study Design: Aim 1 is designed to construct and then characterize an E1B-deleted adenovirus, in which the viral E1A promoter is deleted and E1A gene expression is controled by the DF3-MUC1 promoter and, independently, by the hTERT promoter. Aim 2 is designed to construct a P450-armed, breast cancer replication-selective conditional adenovirus. In Aim 3, the proposed viral construct will be tested in human breast cancer xenografts models, both with localized and systemic administration. The therapeutic efficacy of this new vector will be tested when used alone and in combination with systemic CPA treatment.
Potential Outcomes/Benefits: The P450 prodrug activation gene therapy strategy has been already tested in clinical settings, with very promising results. The proposed combination of targeting approaches is a new multifaceted approach for breast cancer treatment. If validated, the proposed strategy will benefit a sizeable population of breast cancer patients.
Background: Therapeutic viruses can be developed for breast cancer treatment by taking advantage of several characteristics of the tumor phenotype to facilitate tumor-selective viral replication and oncolysis. Such characteristics found in a majority of breast cancers include overexpression of the DF3-MUC1 antigen and the enzyme telomerase, and deficiency of the tumor suppressor gene p53. However, tumor cell subpopulations within a patient, including metastases, may be lacking one or more of these characteristics, and may thereby escape viral oncolysis.
Objective/Hypothesis: Oncolytic viruses tailored to a single breast cancer trait are likely to be only partially effective due to tumor cell heterogeneity within a given patient. It is hypothesized that an oncolytic adenovirus whose replication integrates several breast cancer traits can be developed as an effective treatment for breast cancer. It is further hypothesized that the tumor cell bystander cytotoxicity of this virus can be substantially enhanced by arming the virus with a cytochrome P450 (CYP) prodrug-activating gene that displays high intrinsic activity against the widely used breast cancer chemotherapeutic drug cyclophosphamide (CPA or Cytoxan).
Specific Aims: I propose to construct an oncolytic adenovirus that will selectively replicate in breast cancer cells by taking advantages of three common features of breast cancer cells: DF3-MUCI overexpression, high telomerase activity and p53 deficiency. Furthermore, I will arm this tumor replication-specific virus with a CPA-activating CYP2B11 enzyme, which confers strong tumor cell contact-independent bystander cytotoxicity. Moreover, the high catalytic efficiency of CYP2B11 will help circumvent drug resistance imparted by aldehyde dehydrogenase, which contributes to breast cancer resistance to CPA in the clinic.
Study Design: In the initial phase of this project, I will construct a breast cancer-specific adenovirus, and then test its therapeutic utility and specificity in breast cancer cells in vitro. The effectiveness of this novel oncolytic virus in treating human breast cancer tumors will be evaluated in xenografts grown in rodent models.
Potential Outcomes and benefits of the research: The proposed strategy combines several powerful therapeutic combinations and approaches to breast cancer treatment, several of which have been tested and validated individually in preclinical and clinical testing. If successful, the proposed studies may lead to follow up clinical trials.