Gene Therapy in Radiotherapy of Cancer




Keywords

Radiotherapy, Radioprotection, MnSOD-PL

 




Introduction: The Radiotherapy Update


Radiation therapy (radiotherapy) remains one of the three critical approaches toward the management of the cancer patient, along with surgery and chemotherapy . There are two general categories in the approach toward delivering radiotherapy to cancer cell volumes: brachytherapy (radioactive source implant procedures) and external beam radiotherapy . Brachytherapy involves the application of permanent radiation sources (radium and cesium) using intracavitary or mold application and also interstitial application (using needles, wire, or catheter placement with later temporary insertion of radiotherapy low-dose-rate or high-dose-rate sources) delivered as radiation to localize tissue with the highest dose and dose rate close to each source and the falloff of dose with the square of the distance in centimeters from the source. Techniques of brachytherapy designed during the first half of the 20th century greatly improved the clinical outcomes of many cancer patients, primarily those with head and neck cancer and gynecological malignancies including cervix cancer and endometrial cancer . Both acute and late effects of brachytherapy relate to the total dose delivered, dose rate, and concomitant surgical procedures required to insert and remove sources .


In brachytherapy, radioactive source removal has been alleviated by the use of permanent radioactive seed implantation techniques and by the use of short-lived radioisotopes to deliver localized dose that then decays over days to weeks to radiation levels that are low or undetectable, leaving seeds in place within the tumor requiring no further surgical procedure for removal, which is different from the surgical staple technique.


In contrast to brachytherapy, external beam radiotherapy utilizes focused aiming of one or multiple radiation beams each culminated to combined shape the radiation dose around a tumor volume. The first kilovoltage (ortho-voltage) radiotherapy machines utilized diagnostic X-ray machines , the use of which was often associated with severe skin reactions due to backscatter of low-energy photon energy from the calculated tumor volume depth back to the skin. The advent of the cobalt-60 teletherapy unit in the mid-20th century and modern linear accelerators facilitated dose deposition deep in the tissues with minimal skin reaction . High linear energy transfer particle beam radiotherapy, including protons, neutrons, and, recently, carbon atom accelerators, further facilitated precise focus of irradiation dose deep into tissues with a relative decrease in normal tissue dose. Finally, a sophisticated computer-driven X-ray (photon) delivery system utilizing moving collimators, moving treatment machine gantries, and techniques of image-guided radiotherapy (in which computed tomography (CT) scans or diagnostic-quality X-rays are matched to the radiotherapy beam) allows focus delivery of multiple photon beam radiotherapy . The toxicity to normal tissues is determined by the number of radiotherapy fractions (number of treatments during 6 or 7 weeks), dose delivered per treatment, overall treatment time and days, and volume of normal tissue treated.


By the mid-20th century, parameters for safe delivery of therapeutic irradiation using either brachytherapy or external beam radiotherapy had been well-established. The advent of combination chemotherapy, using increasingly effective cytotoxic drugs and, recently, biological response modifiers, has required modification of the “safe” parameters for radiation therapy because normal tissue toxicity increased with the improvement in tumor control . The therapeutic setting is even further complicated by the wealth of new date from positron emission tomography/CT scanning and sophisticated cancer cell imaging techniques, which have allowed identification of microscopic disease in both adjacent and distant locations from the primary tumor. This necessitates discussions of how large a volume of tissue to treat and whether the focus should be on stereotactic radiosurgery (high dose, high dose rate, and pencil-diameter beam delivery to nodal areas) .


Finally, use of total body irradiation to prepare leukemia, multiple myeloma, and other solid tumor patients for bone marrow transplantation or for uses with additional “systemic” chemotherapy agents provides the ultimate challenge to radiation oncologists with respect to improving the therapeutic ratio . In the case of total body irradiation, shielding of normal tissues such as lung with transmission block fractionating irradiation or lowering the dose rate can decrease toxicity, but they also increase the likelihood of tumor recurrence .




Gene Therapy Approaches to Enhance Management of the Radiotherapy Patient


The discovery of oncogenes and tumor suppressor genes and the identification of gene translocation specifically within tumor cells provide a challenge to adapt gene therapy techniques to cancer patients. Accordingly, the first gene therapy strategies targeted tumor cells in an attempt to counterbalance or overload abnormal cancer cell-specific gene expression with “normal” gene expression. In the case of p53 , gene deletion, or blocked expression of gene product, lung cancer patients provided a logical target for insertion of wild-type p53 transgene. Furthermore, lung cancer tumor localization by diagnostic radiographs and transgene insertion through stereotactic thoracic surgical techniques facilitated successful clinical trials . The same strategy held for head and neck cancers found to contain mutated epidermal growth factor receptors (EGFRs), facilitating a clinical trial in which insertion of wild-type EGFR localized surgical injection techniques followed .


Therapeutic transgene application to tumor targets also included approaches in which an additive or synergistic cytotoxic agent could be inserted by localized surgical technique. Prostate cancer target volume treated with herpes simplex virus-activated cytotoxin was found to be of therapeutic benefit combined with external beam radiotherapy. Ionizing irradiation-activated promoters linked to transgenes provided an ideal method by which to localize transgene activation in tumor volumes within the radiotherapy beam.


Although all tumor-specific gene therapy approaches provided attractive model systems, and many were successfully translated to the clinic, a common problem was the difficulty in finding a vector to facilitate transgene expression in a significant number of tumor cells within a target volume . Other concerns were the role of tumor vasculature , the role of supportive stromal cells , and the effect of infiltrating immune cells in both the response to the transgene product and its interaction with ionizing irradiation . Gene therapy successes in targeting vascular structures in other noncancer diseases gave encouragement to the field. Localized injection of transgene into tumor volume necessitated localization of tumor, targeting with insertion devices, and the attendant trauma associated with localized gene delivery. This strategy was most obvious with head and neck and lung cancer and brain tumors . Hemorrhage was a risk and could have resulted from inserting needles to allow localized expression of transgene . Irradiation late effects, primarily fibrosis or scarring, were a concern for possible deleterious additive toxic effects of gene delivery to tumors . An alternative approach of systemic (intravenous) delivery of transgene, while avoiding localized traumatic insertion techniques, created the new problem of transgene expression in surrounding tissues within the radiotherapy target volume or distant sites . A significant concern was the possible higher level of expression of a radiosensitizing transgene product in normal tissues compared to tumor—a situation that could tip the therapeutic ratio in the wrong direction, producing later radiotherapy toxicity . Finally, the use of fractionated irradiation in external beam approaches and the limited degree of expression of the transgene necessitated multiple transgene administrations , which were impractical in cases of surgical operative locations for injection to sustain bioavailability of gene product.


With all of the concerns for potentially critical toxicities, new approaches have focused on the identification of transgene products that would be more toxic to cancer cells compared to normal tissues. For example, in the case of improved tumor cell survival under hypoxic conditions, delivery of transgene products specifically toxic to hypoxic cells (HIF1 inhibitor), presumably nontoxic to normal tissues, might be a strategy for tumor-specific transgene targeting. Figure 9.1 shows the normal tissue of the lung separate from a lung cancer. The insert shows tumor cells, blood vessel endothelial cells, stromal cells, immune cells, and the problem of targeting the tumor for transgene expression.




Figure 9.1


Potential problems with transgene radiosensitization for lung cancer patients undergoing radiotherapy.




Normal Tissue Radioprotective Gene Therapy: The Logic of this Reverse Strategy


Since the initial use of radiotherapy in the management of cancer patients, normal tissue side effects have been of great importance in choosing radiotherapy dose, beam energy, and daily fraction size . Symptoms of radiation toxicity are treated with palliative measures until a therapeutic (tumoricidal) dose is achieved or the intensity of radiotherapy side effects prevents completion of the treatment plan. The best approach toward normal tissue protection has been, and continues to be, the blocking of normal tissues by precise radiotherapy beam columniation. There has been replacement of 10 half-value layer lead blocks with movable multileaf collimators .


The concept of radioprotective gene therapy for normal tissues followed studies that designed small molecule normal tissue radioprotectors . Studies during the 1970s at the Walter Reed Research Institute led to the discovery of WR2721 , a free radical scavenger compound now therapeutically known as amifostine . Systemic and organ-specific delivery of the radioprotector amifostine showed some positive therapeutic effects. Most prominent has been the clear demonstration of protection of the salivary glands and reduction of xerostomia in head and neck cancer patients receiving amifostine , attributable to the high concentration of drug in salivary glands. Attempts to use locally applied amifostine to protect rectal tissue to increase the efficiency of radiotherapy of prostate cancer, or swallowed amifostine to treat the esophagus or inhaled or systemic drug to protect normal lung, have had less therapeutic success. The strategy of normal tissue radioprotection using small molecules led to the concept that gene therapy could also be used for normal tissue protection and offered the added potential advantage of transient—but perhaps lasting several days—continuous production of transgene transcript and protein that is perhaps more effective and long enough in duration for clinical radioprotection .


Identification of targets for normal tissue radioprotection using gene therapy originated with an analysis of the components of the normal tissue response to irradiation. Figure 9.2 shows potential targets for development of a transgene therapy for radioprotection of normal tissues (DNA strand breaks, nucleus-to-mitochondrial targeting, apoptosis, cell death, cytokine elaboration, and secondary cell death). Strategies by which to prepare transgenes targeting DNA repair, to lessen DNA strand breaks, were difficult due to the nonspecificity of transgene uptake in normal compared to tumor tissue. Strategies to target cytokine production by irradiation-damaged cells to prevent secondary normal tissue apoptosis were also difficult because they needed to avoid tumor radioprotection. A promising strategy was that associated with gene therapy approaches to target the oxidative stress response of normal tissue compared to cancer cells to ionizing irradiation, specifically the apoptotic cellular pathway .




Figure 9.2


Potential targets for normal tissue radioprotective gene therapy.


Pioneering studies by Biaglow et al . and Bump et al . demonstrated that the ionizing irradiation-induced DNA strand breaks were followed by rapid depletion of antioxidant stores, prominently glutathione, within cells. Irradiation also induced high levels of antioxidant enzymes , including the superoxide dismutases . A major advancement in the understanding of radiation-induced cell death in normal tissues was the identification of the role of communication between nuclear DNA strand breaks and mitochondrial mechanisms of apoptosis . Irradiation-induced DNA strand breaks are followed immediately by phosphorylation of the ATM protein and establishment of a DNA repair complex at the site of strand breaks involving genes within the Fanconi pathway and those associated with homologous recombination and nonhomologous end joining . Following DNA strand breaks and initiation of DNA repair, proteins are translocated from nucleus to mitochondria, including those of the stress-activated protein kinase pathway , JNK1, p38, as well as cell cycle regulatory proteins p53 and p21 . The mitochondrial membrane interaction of pro-apoptotic (BAX) and anti-apoptotic (BCLXL and BCL2) proteins establishes a balance that is tipped either toward ion channel stabilization to limit mitochondrial membrane permeability and stabilize the mitochondrial membrane or toward destabilization . Protein interactions altering the mitochondrial membrane occur simultaneously with changes in free radical production . Prominent in the cascade of radiation-induced free radicals is the interaction between superoxide and nitric oxide . The combination of superoxide with nitric oxide forms peroxynitrite, a potent initiator of lipid peroxidation .


Data indicate that stable interaction between cytochrome c and cardiolipin within the mitochondrial membrane is critical to stabilize the mitochondria from initiating apoptosis . Oxidative stress at the mitochondria produces multiple negative and destabilizing changes in the antioxidant pool . One change is the conversion of cytochrome c into a peroxidase that oxidizes cardiolipin and facilitates its separation from cytochrome c. Cytochrome c then releases from the mitochondrial membrane during oxidative stress-induced changes and initiates activation of the caspase system and apoptosis . Another change induced by oxidative stress in the mitochondria is the nitration of superoxide dismutase (SOD), which converts this antioxidant enzyme into a peroxidase . Oxidized SOD, even in a tetrameric form, continues to neutralize superoxide, whereas the nitrated form destabilizes the antioxidant pool . Knowledge of free radical biochemistry at the mitochondria and mitochondrial membrane presented multiple targets for potential gene therapy approaches for radioprotection of normal tissues .




Practical Applications: MnSOD-Plasmid Liposome Gene Therapy


The concept of using an antioxidant transgene for radioprotection of normal tissues derives from an understanding of the normal tissue radiation response. Pioneering studies by multiple groups, including those led by Philip Rubin , Lawrence Marks , and Michael Anscher , demonstrated that irradiation of normal tissue upregulates a series of proteins, including several termed inflammatory cytokines and “early response genes.” Upregulation of interleukin-1, tumor necrosis factor-α, transforming growth factor-β, and interferon-γ was demonstrated to occur both in tissues within irradiated fields and in peripheral blood cells and distant sites. Further studies demonstrated that other categories of gene transcripts and gene products were also elevated in the immediate minutes to hours after ionizing irradiation exposure . Some of these gene products in the irradiation response were common to other oxidative stress pathways, including ischemia reperfusion injury, hyperthermia, hypoxia, and response to chemotherapeutic toxic agents .


One category of genes upregulated in the ionizing irradiation response was that of the cellular oxidative stress response . Prominent among the genes associated with the oxidative response was manganese superoxide dismutase . MnSOD (SOD2) is one of three superoxide dismutases functioning to neutralize superoxide, a free radical induced by ionizing irradiation. Unlike cytosolic SOD1 and extracellular SOD3, MnSOD (SOD2) has a mitochondrial targeting peptide that localizes the protein to the mitochondrial membrane . Initial studies transfecting hematopoietic progenitor cell line 32D cl 3 demonstrated that SOD2, in its intact form but not in a form deleting the mitochondrial targeting sequence, significantly increased radioresistance of cells in culture . In reciprocal experiments, Cu/ZnSOD (SOD1) was ineffective as a radioprotector, but when linked to the mitochondrial localization sequence of MnSOD, it became a potent radioprotector . These in vitro studies led to translation of the use of MnSOD transgene therapy to clinical radiation protection.


Initial radioprotection studies of MnSOD transgene used plasmid liposomes (PL) and adenovirus for radioprotection of the lung . Due to the inflammatory response to adenovirus , the less toxic PL approach was taken. Amelioration of late radiation fibrosis/organizing alveolitis in the C57BL/6J mouse model demonstrated that intratracheal injection or inhalation of MnSOD-PL using an aerosol in a nebulizer device produced significant uptake of epitope tagged MnSOD in alveolar type II cells, pulmonary alveolar macrophages, and endothelial cells of the lung . In contrast, there was significantly less uptake of MnSOD transgene and product expression in orthotopic tumors in the mediastinum or lung, and there was no significant radiation protection of these orthotopic tumors .


Reports by Oberley et al . and St. Clair et al . indicated that squamous cell tumors originating in several different anatomic sites demonstrated a downregulation of MnSOD due to mutation in the promoter region or other defects in transcription and translation. The downregulation of MnSOD in tumors conferred an inability of these tumor cells to biochemically degrade hydrogen peroxide, the product of MnSOD dismutation of irradiation-induced superoxide , because peroxidase was also downregulated. Consistent with these observations was a report that glutathione peroxidase , the biochemical mediator of H 2 O 2 metabolism to water, was downregulated in human tumors. In this study, Oberley et al . demonstrated that transfection of tumor cells with a transgene for MnSOD produced hydrogen peroxide that was toxic to tumor cells and had no toxic effect on normal tissue cells that had an intact MnSOD pathway. Transfection of a glutathione peroxidase transgene (to mediate biochemical degradation of hydrogen peroxide to water) along with the MnSOD transgene reversed the toxicity of hydrogen peroxide in tumor cells .


Data on orthotopic lung tumors and head and neck cancers confirmed and extended the observations by Oberley et al . demonstrating that local administration of MnSOD-PL significantly protected the normal lung, esophagus, oral cavity, tongue, and oropharynx while having significantly less effect on orthotopic tumors. The therapeutic effect was mediated by a difference in antioxidant pool size in normal tissues compared to tumors and also by the hypersensitivity of tumor cells to hydrogen peroxide in comparison to normal tissues . The successful application of intratracheal or inhalation delivery of MnSOD-PL gene therapy led to studies confirming the effectiveness of the MnSOD transgene as a radioprotector for esophagus , oral cavity and oral mucosa , bladder , intestine , pregnant mice , bone wound healing , and total body irradiation (TBI) . In TBI studies, MnSOD transgene, delivered by plasmid liposomes, was shown to localize in the liver as well as other tissues and to confer significant radioprotection against both the acute and the chronic effects (life shortening) of TBI . When added to an antioxidant diet in the post-irradiation period, further improvement in late effects of TBI (decreased life shortening) was observed .


The previously mentioned studies demonstrated the potential effectiveness of antioxidant gene therapy in the treatment of squamous cell tumors and also in the normal tissues from TBI.




Future Directions in and Applications of Gene Therapy in Radiation Oncology


What would be the ideal gene therapy application in radiation oncology? Several investigators have suggested one that would combine the following five principles of gene therapy:



  • 1.

    Use of targeting transgene to the tissue/organ of interest with gene expression in an adequate number of cells to provide therapeutic effect in the setting of ionizing irradiation


  • 2.

    Minimal toxicity for normal tissues


  • 3.

    Safety of the methodology, meaning rapid elimination of the transgene product from normal tissues with no delayed deleterious effect on somatic cells or germ cells, no transmission of gene product through the germline, and effective elimination of the gene product with death of tumor cells


  • 4.

    In the setting of tumor radiosensitization, activation of the transgene product specifically in tumors by ionizing irradiation directly or indirectly through the radiation-induced bystander effect


  • 5.

    In the setting of normal tissue radioprotective gene therapy, utilization of a transgene product that would have no protective effect on tumor cells and ideally could provide simultaneous tumor radiosensitization



Two groups of investigators have published clever approaches to achieve some or all of these goals . There have since been successes both in animal studies and in clinical trials .


Future research in gene therapy approaches to radiotherapy will benefit from the availability of new and safe vectors for therapeutic use, including lentiviral vectors for transducing hematopoietic cells in tumors and “safe” non inflammatory adenovirus vectors , adeno-associated viral vectors , and the availability of tissue-specific lipid formulations and emulsions to deliver transgenes . All these studies have advanced the field of gene therapy. Future successes will be dependent not only on the safety of new therapeutics but also on further understanding of tumor biology. Advances in understanding the oncogenic process in specific tumors, including identification of EGFR receptor mutations in lung cancer, K-Ras-overexpressing adenocarcinomas, tumor categories with specific gene deletions, chromosome translocations, and changes altering cell membrane physiology including redox balance, have provided targets not only for small-molecule therapeutics but also for gene therapy approaches.


With respect to the use of radiotherapy in managing primary tumors in close anatomic proximity to critical organs (lung cancer located near heart and spinal cord, spinal cord tumors, esophageal cancer, brain tumors, pancreas cancer, and others), new insight has been gained from studies of the tumor microenvironment. Primary cancers contain not only malignant cancer cells (including quiescent cancer stem cells and differentiated progeny) but also a network of stromal cells, endothelial cells, and inflammatory response cells including macrophages, subsets of T lymphocytes, actual killer cells, and mononuclear leukocytes ( Figure 9.1 ). Innovative gene therapy approaches include using cells of the tumor microenvironment to carry transgenes into the tumor. Granulocyte macrophage colony-stimulating factor transgene expressing cells injected into the tumor stimulate leukocytes to migrate to the tumor. Also, strategies that use gene therapy to limit growth of the cellular support elements of the tumor microenvironment are examples of new approaches. Limiting tumor neovasculature growth by endothelial cell targeting and using growth factor-producing bone marrow stromal cells (mesenchymal stem cells) to carry transgenes into tumors to limit tumor growth or increase the tumor response to ionizing irradiation are two other ideas.


The disciplines involved in cancer therapy now have new novel approaches for combined modality therapy including gene therapy. Further studies will be required to define the ideal gene therapy targeting system to optimize the outcomes of radiotherapy of cancer patients.


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