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    Awarded Grants
    Preclinical Models for Treatment of Residual Neoplastic Disease

    Scientific Abstract:
    Preclinical Models for Treatment of Residual Neoplastic Disease Background: A cardinal feature of human breast cancers is the survival and persistence of residual neoplastic cells long after the apparently successful treatment of the primary tumor. Indeed, over a third of breast cancers in women recur more than 10 years following treatment of the primary tumor. Ultimately, residual neoplastic cells re-emerge from this dormant state and resume growth, leading to cancer recurrence. To better understand the mechanisms of breast cancer recurrence, we have created a novel bitransgenic mouse model system in which the oncogenes c-MYC and activated Neu/ErbB2 can be inducibly expressed in the mammary epithelium of animals treated with tetracycline derivatives. Following induction with doxycycline, bitransgenic animals expressing either c-MYC or Neu develop invasive mammary adenocarcinomas. Surprisingly, we have found that the majority of oncogene-induced primary mammary tumors regress to a non-palpable state following doxycycline withdrawal and oncogene down-regulation. However, despite this dramatic regression behavior, a substantial fraction of tumors that have previously regressed to a non-palpable state recur spontaneously in the absence of transgene expression over periods of up to one year. Moreover, additional studies from our laboratory demonstrate that essentially all animals bearing fully regressed tumors harbor residual neoplastic disease long after the apparently complete regression of their tumors. Our findings suggest that this may represent a valuable new model system for residual neoplastic disease that can be used to understand the biology of residual neoplastic cells and to identify treatments that may prevent breast cancer recurrence. Objective/Hypothesis: The objective of this study is to use the novel inducible transgenic models for residual neoplastic disease that we have developed to identify therapeutic interventions capable of reducing mammary tumor recurrence, either by eliminating the residual neoplastic disease that leads to tumor recurrence or by preventing the outgrowth of residual neoplastic cells. Specific Aims and Study Design: This application will use transgenic models for residual neoplastic disease to test therapeutic agents for their efficacy in reducing the recurrence of fully regressed c-MYC or Neu-induced mammary tumors. The first specific aim of this study is to determine whether TGF-beta pathway inhibitors, EGF receptor inhibitors, RXR-selective retinoids, or ionizing radiation are able to prevent or delay spontaneous tumor recurrence in animals harboring fully regressed mammary tumors. This will be accomplished by treating animals bearing fully regressed c-MYC or Neu-induced mammary tumors with these agents and determining their effect on the incidence and latency of spontaneous tumor recurrence. The second specific aim of this study is to determine whether these same agents are able to reduce the burden of residual neoplastic disease in animals harboring fully regressed mammary tumors. This will be accomplished by treating animals bearing fully regressed c-MYC or Neu-induced mammary tumors with these agents and then monitoring for recurrent tumor growth after reinducing transgene expression with doxycycline. Potential Outcomes and Benefits of Research: The survival and persistence of residual neoplastic cells after the apparently successful treatment of primary breast cancers is an important obstacle to the clinical management of this disease, since breast cancer recurrence is a major cause of mortality. As such, there is a desperate need for preclinical models that faithfully recapitulate key features of residual neoplastic disease and breast cancer recurrence in humans. The transgenic system that we have developed models important aspects of the natural history of human breast cancer and should help to identify specific therapeutic interventions capable of preventing breast cancer recurrence. Ultimately, this approach should facilitate the development of more effective therapeutic approaches to this disease.

    Lay Abstract:
    Preclinical Models for Treatment of Residual Neoplastic Disease Background: A cardinal feature of human breast cancers is the survival and persistence of residual cancerous cells long after the apparently successful treatment of the primary tumor. Indeed, over a third of breast cancers in women recur more than 10 years following treatment of the primary tumor. Ultimately, residual cancerous cells re-emerge from this dormant state and resume growth, leading to cancer recurrence. As such, identifying approaches to preventing tumor recurrence is a critical priority in breast cancer research. Unfortunately, few if any experimental models for this phenomenon currently exist. The oncogenes HER2/NEU and c-MYC are each amplified in 10-30% of human breast cancers and in each case amplification is associated with aggressive tumor behavior, tumor recurrence, and poor patient outcome. The molecular mechanisms by which breast cancers recur in humans are unknown. To better understand this phenomenon, we have created novel transgenic mouse models that permit the oncogenes c-MYC or an activated version of Neu to be turned on in the mammary glands of transgenic mice that have been treated with the antibiotic, doxycycline. Following induction with doxycycline, transgenic animals expressing either c-MYC or Neu develop invasive mammary cancers. Surprisingly, we have found that the majority of oncogene-induced primary mammary tumors regress to a non-palpable state following doxycycline withdrawal and oncogene down-regulation. However, despite this dramatic regression behavior, a substantial fraction of tumors that have previously regressed to a non-palpable state recur spontaneously in the absence of transgene expression over periods of up to one year. These findings suggest that many animals in whom tumors have regressed still harbor residual cancerous disease and that additional genetic events may occur in these remaining cells that lead to the recurrence of actively growing tumors. As such, this mouse model system parallels the natural history of human breast cancer and highlights the importance of identifying the molecular mechanisms by which c-MYC and Neu-induced tumors escape their dependence on these oncogenes for growth. We believe that the model system that we have developed could represent a valuable new means to understand the biology of residual breast cancer cells and to identify treatments that may prevent their recurrence. Objectives: The objective of this study is to use the novel transgenic mouse models for residual neoplastic disease that we have developed to identify therapies capable of reducing breast cancer recurrence, either by eliminating the residual cancerous cells that lead to tumor recurrence or by preventing the outgrowth of these cells. Specifically, we will test several new molecularly targeted therapeutic agents for their ability to reduce the recurrence of fully regressed c-MYC or Neu-induced mammary tumors. These drugs target molecular pathways that have been shown to be important for the growth of breast cancer cells and that we hypothesize may be involved in breast cancer recurrence. We will determine whether these agents are able to reduce breast cancer recurrence, and whether they are able to reduced the number of residual cancerous cells that are left in the breast following the initial regression of c-MYC and Neu-induced cancers. Potential Outcomes and Benefits of Research: The survival and persistence of residual cancerous cells after treatment of the initial tumor is a major obstacle to breast cancer management, since tumor recurrence frequently leads to mortality. As such, there is a desperate need for model systems that faithfully recapitulate key features of residual neoplastic disease and breast cancer recurrence in humans. The transgenic system that we have developed models important aspects of the natural history of human breast cancer and should help to identify specific therapeutic interventions capable of preventing breast cancer recurrence.