Ruth Gjerset Ph.D.

Lay Description

There is an urgent need for efficient, non-toxic biological therapies for lung cancer, particularly for advanced disease, where current therapies are often inadequate. Tumor suppressor gene therapy involving the p53 and p14ARF tumor suppressor genes is highly suppressive of lung cancer cells. However, presently available gene delivery vehicles are rejected by the immune system if they are administered through the blood stream (systemically). This is true of the widely used adenovirus (a type of cold virus) that has been modified to carry the p53 gene, and which is presently being evaluated in clinical trials. The p53 adenovirus and other current gene delivery vehicles work best for local treatment of isolated tumors, and do not adequately address the problems of disseminated, metastatic disease where systemic delivery of the genes would be required. An efficient systemic gene delivery method would enable us to fully exploit the therapeutic potential of the p53/p14ARF gene combination for early or advanced lung cancer and provide a highly effective, cancer-specific, non-toxic way to suppress all or most lung cancers.

We want to develop a systemic gene delivery strategy that uses mesenchymal stem cells. Mesenchymal stem cells are derived from the bone marrow and contribute to tissue regeneration. We have shown that they can be engineered to produce adenovirus. Because they are not rejected by the immune system and can be administered systemically, and because they migrate to tumors and preferentially integrate there, they are attractive as therapy-delivery vehicles for primary or advanced cancers. We hypothesize that these cells can be used to deliver therapeutic p53/p14ARF adenovirus to advanced lung cancer and suppress the disease.

We have already generated Mesenchymal stem cells capable of producing adenoviral particles of the type used for therapy. We have also constructed a therapeutic adenovirus that includes the p53 and p14ARF tumor suppressor genes. We will use a preclinical model for lung cancer to examine the ability of Mesenchymal stem cells to migrate to lung tumors and to disseminate within the tumor. We will then test the anti-tumor activity of mesenchymal stem cells engineered to produce the p53/p14ARF adenovirus and carry it to tumors.

Mesenchymal stem cell-based delivery of the p14ARF and p53 tumor suppressor genes is a highly innovative and novel approach to gene delivery. If successful, it could establish an entirely new approach to tumor suppressor gene therapy for lung cancer and have a major impact on treatment for advanced disease. Gene-based therapeutic strategies are among the most specific and potentially most effective and least toxic ways to treat cancer. A cell-based strategy for targeting therapeutic tumor suppressor genes to lung tumors, addresses the need for highly effective, minimally toxic treatments, that preserve quality of life while providing for long-term survival.

Scientific Abstract

There is an urgent need for targeted biological therapies for lung cancer with greater efficacy and less toxicity, particularly for metastatic disease. The p53/p14 pathway is an ideal point of focus because it is likely to be disabled in virtually all lung cancers, and restoration of the pathway through adenoviral-mediated p14ARF/p53 gene transfer is highly suppressive of lung cancer growth. While adenoviral vectors may provide local control of tumor growth, they do not address the broader problem of metastatic disease, where systemic delivery approaches are required, and where novel therapies are most urgently needed. Because p14ARF/p53-based strategies could provide greatly improved treatments for advanced and disseminated cancers, it is essential to develop ways to extend gene delivery strategies to theses cancers as well.

This study will establish a rationale for a novel mesenchymal stem cell (MSC)-based therapy that delivers the p14ARF and p53 tumor suppressor genes systemically to primary lung tumors or to multiple metastatic sites. We have prepared MSC adenoviral packaging cells. We hypothesize that these cells could be used to target p14ARF/p53 bicistronic adenoviral vectors to tumors. By exploiting the property of MSCs to integrate preferentially into tumors following systemic administration, and by tapping into the potent anti-tumor activity of the p53/p14ARF gene combination, this approach could circumvent the obstacles to efficient gene delivery encountered with current gene delivery approaches, and provide an effective, non-toxic therapeutic alternative for metastatic disease.

Using a nude model dorsal skin-fold chamber model for lung cancer we will (1) Examine the intratumoral dissemination and tumor tropism of MSCs compared to free adenoviral particles following local (intrachamber) or systemic delivery to tumor-bearing model, and (2) Evaluate and compare the antitumor activity of free bicistronic adenoviral particles encoding p14ARF and p53 in tandem (Adp14/p53) to that of MSCs engineered to deliver Adp14/p53.

We have prepared an MSC packaging line for replication-defective adenovirus and a replication-defective adenoviral vector encoding p14ARF and p53 (Adp14/p53). We will use a nude model dorsal skin-fold chamber model for lung cancer based on murine Lewis lung cancer cells, followed by fluorescence video microscopy to visualize intratumoral dissemination of MSCs and to follow anti-tumor effects of Adp14/p53, delivered as a free vector, or delivered via the MSC vehicle.

If successful, this approach will offer a means to achieve long-term or permanent suppression of advanced cancers that have failed to respond to conventional therapies, and will establish a rationale for an entirely new strategy for targeted, cancer-specific gene-based therapies that could have a major impact on lung cancer survival. Gene-based therapies are among the most specific and potentially most effective and least toxic ways to treat cancer. A cell-based gene delivery strategy that targets therapeutic tumor suppressors to metastatic lung cancer would provide a highly effective, minimally toxic therapy that preserves quality of life while providing for continued long-term survival.