Novel therapeutic approaches represent the latest advances in targeted cancer therapy that may one day provide clinicians with a better means of custom-tailoring cancer treatment. Eventually, treatments may be individualized based on unique sets of molecular targets.
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BIO-BUZZâ–º New Research Targets “Natural” Biological Systems Via Cancer-Killing Viruses, Gene Therapy and Agents That Affect Cellular Signaling Pathways
Targeted cancer therapies use drugs that block the growth and spread of cancer. They interfere with specific molecules involved in carcinogenesis and tumor growth. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells. Targeted cancer therapies interfere with cancer cell growth and division in different ways and at various points during the development, growth, and spread of cancer. Many of these therapies focus on proteins that are involved in the signaling process. By blocking the signals that “tell” cancer cells to grow and divide uncontrollably, targeted cancer therapies can help to stop the growth and division of cancer cells.
Targeting specific defects in cancer has been the focus of cancer researchers for the better part of a decade. At the annual meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007, the results of several studies that examined the therapeutic potential of targeting specific biologic systems were presented. These novel therapeutic strategies included the use of gene therapy, cancer-killing viruses, and agents that affect cellular signaling pathways.
Cancer-Killing Viruses and Gene Therapy for the Treatment of Prostate Cancer: A Dual-Targeting Approach
Devanand Sarkar, MBBS, PhD and colleagues at Columbia University, New York, NY studied a dual cancer-specific targeting strategy that facilitated the eradication of both primary and distant resistant prostate cancers.1 They infected xenografts derived from athymic nude mice with Ad.PEG-E1A-mda-7, an adenovirus in which the expression of adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of the progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the virus.
Overexpression of Bcl-2 or Bcl-xL is frequently observed in patient-derived prostate cancer samples and is associated with resistance to conventional therapy.2 Infection of Ad.PEG-E1A-mda-7 in normal prostate epithelial cells and prostate cancer cells, including Bcl-2— or Bcl-xL–overexpressing cells such as Du-145-Bcl-xL, PC-3-Bcl-xL and LNCaP-Bcl-2, confirmed cancer cell–selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into xenografts derived from Du-145-Bcl-xL cells in athymic nude mice completely eradicated both the primary tumor and distant tumors (established on the opposite flank of the animal). The dual cancer-specific targeting strategy facilitated the eradication of both primary and distant resistant prostate cancers, thereby demonstrating potential for translational application of this strategy for treating terminal prostate cancer patients.
Gene therapy may eventually be used against cancer in a variety of ways. Strategies under investigation include: (1) adding functioning genes to cells that have abnormal or missing genes; (2) preventing oncogenes or other genes important in the pathogenesis of cancer from working; (3) adding genes to cancer cells to make them more vulnerable to chemotherapy or radiation therapy; (4) adding genes to tumor cells so they are more easily detected and destroyed by the body’s immune system; and (5) stopping genes that play a role in angiogenesis, or adding genes that stop it.
According to Dr. Sarkar, “The beauty of this approach is that two methods are being used to destroy a tumor. The virus we designed replicates within a tumor, and at the same time produces a massive amount of a cancer-killing compound. Either action alone is damaging and potentially deadly, but together they are lethal.”
Added Dr. Sarkar, “When the viral gene therapy was injected into tumors growing in the mice, the virus replicated and produced mda-7/IL-24, which then killed the tumors, releasing millions of newly produced, loaded viral particles throughout the blood circulation to settle into distant tumors, where the process was repeated. It also worked on prostate cancer resistant to other therapy because the two-pronged attack overwhelmed their defense mechanisms.”
These results are exciting, but additional research is needed prior to evaluate the dual approach in animal models and in humans. While a primary immune system response against the virus may eliminate some of the loaded particles, the researchers say that the mda-7/IL-24 will likely heighten a secondary therapeutic immune response, offering a much stronger cancer-killing potential.
Angiogenesis Inhibition for the Treatment of Glioblastoma Multiforme
Despite advancements in therapy over the last decade, recurrent glioblastoma remains a uniformly fatal disease. One of the hallmarks of glioblastoma is endothelial proliferation; hence, anti-angiogenic agents, which have been employed for the therapy of other solid tumors, may be a promising therapeutic class in glioblastoma. Tracy Batchelor, MD and colleagues at the Massachusetts General Hospital (MGH) and Dana Farber Cancer Institute, Boston, MA performed a prospective study of AZD2171 (Recentin®, AstraZeneca), an oral tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptors, in 29 consecutive patients with recurrent glioblastoma multiforme.3
Angiogenesis inhibitors suppress the growth of blood vessels supplying a tumor and have received a lot of attention as potential anti-cancer agents. Although early clinical trials did not meet expectations that these drugs would starve tumors of their blood supply, angiogenesis inhibitors did improve patient survival when combined with traditional anticancer therapies. Three such drugs have received FDA approval for the treatment of certain tumors, and several others are under investigation. AZD2171, which is administered orally, is a potent inhibitor of the three primary receptors for the powerful angiogenesis factor VEGF, known be present on glioblastoma blood vessels.
The MGH trial, sponsored by the National Cancer Institute, was designed to assess whether AZD2171 could benefit patients with recurrent glioblastoma and also if the drug might normalize tumor vasculature. Blood vessels that develop around and within tumors are leaky and disorganized, potentially blocking the delivery of chemotherapy drugs or the effectiveness of radiation therapy, which requires an adequate supply of oxygen to the tumor. The fact that combining angiogenesis inhibitors with other therapies improved survival for some patients supports a theory developed by Dr. Rakesh K. Jain, also of the MGH, that anti-angiogenic agents transiently “normalize” the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery, thereby creating a period during which chemotherapy and radiation treatment may be more effective.4
The investigators used magnetic resonance imaging (MRI) to evaluate tumor vessels after administration of AZD2171. They noted that reversal of vascular normalization began by 28 days, and some features persisted for as long as 4 months. Blood-biomarker studies allowed the investigators to track what was happening in the tumors. They noted that as expression of VEGF proteins decreased, levels of two other proteins—fibroblast growth factor (FGF) and stromal cell—derived factor 1 alpha (SDF1α)—increased as the tumor switched to other pathways. According to Dr. Batchelor, Chief of Neuro-Oncology at Massachusetts General Hospital and lead investigator of the study, “We all recognize that what we need to do now is combine this therapy with other types of treatments, either existing or to be developed, and to deliver these drug combinations during the window we have identified. This might help us manage patients much more effectively.”
This was the first study to identify the onset and duration of a vascular normalization window created by an anti-angiogenic agent in any human tumor. The results provide the first evidence that recurrent glioblastoma remains responsive to anti-angiogenic therapy following progression during drug interruption, and suggest that the timing of combination therapy may be critical for optimizing activity against glioblastoma. Finally, this study demonstrated that AZD2171, a multitargeted tyrosine kinase inhibitor, can alleviate edema, a major cause of morbidity in glioblastoma, and is associated with a corticosteroid-sparing effect in these patients.
Added Dr. Batchelor, “This was not a randomized study, but compared to historical benchmarks, in which response to conventional therapies is approximately 10% and progression is usually 63 days. These results are encouraging.”
â–º Δ-9 Tetrahydrocannabinol for the Treatment of Non—Small-Cell Lung Cancer
Many lung cancers over-express epidermal growth factor receptor (EGFR), and are usually highly aggressive and resistant to chemotherapy.5 Recent studies have shown that Δ-9 tetrahydrocannabinol (THC), the major component of Cannabis sativa, may possess anti-tumor properties against both solid and hematologic malignancies.6,7 However, not much is known about its effect on lung cancer.
Anju Preet, PhD, Division of Experimental Medicine, Harvard University, Boston, MA, and colleagues preformed a series of preclinical studies to evaluate the effect of THC in lab and animal models of lung cancer.8 They endeavored to characterize the effect of THC on EGF-induced growth and metastasis of human non—small-cell lung cancer (NSCLC) cell lines A549 and SW-1573. The investigators showed that these cell lines and primary tumor samples derived from lung cancer patients expressed cannabinoid receptors CB1 and CB2, the known targets for THC action. They also demonstrated that THC inhibits EGF-induced growth in these cell lines. THC attenuated EGF-stimulated chemotaxis and chemoinvasion.
In a murine lung cancer model, A549 cells were implanted in SCID mice (n=6 per group) through subcutaneous and intravenous injections to generate subcutaneous and lung metastatic cancer, respectively. THC (5 mg/kg) was administered once-daily via intraperitoneal injections for 21 days. The mice were analyzed for tumor growth and lung metastases. Significant reductions (~50%) in tumor weight and volume were observed in THC-treated animals compared to vehicle-treated controls. THC-treated animals also showed a significant (~60%) reduction in macroscopic lesions on the lung surface in comparison to vehicle-treated controls. Immunohistochemical analysis of the tumor samples from the THC-treated animals revealed antiproliferative and anti-angiogenic effects of THC, with significant reduction in staining for Ki67 (a proliferative marker) and CD31 (an endothelial marker indicative of vascularization).
Evaluation of the signaling events associated with reduced EGF-induced functional effects revealed that THC also inhibited EGF-induced Akt phosphorylation. Akt is a central signaling molecule of EGFR-mediated signaling pathways that regulates a diverse array of cellular functions, including proliferation, angiogenesis, invasion, and apoptosis.9
The investigators concluded that THC appears to have antitumorigenic and antimetastatic effects against lung cancer, and suggested further research be done to more fully elucidate the potential role of cannabinoids in the treatment of lung cancer. According to Dr. Preet, “The beauty of this study is that we are showing that a substance of abuse, if used prudently, may offer a new road to therapy against lung cancer. When the cells are pretreated with THC, they have less EGFR-stimulated invasion as measured by various in-vitro assays. There was also about a 60% reduction in cancer lesions on the lungs in these mice as well as a significant reduction in protein markers associated with cancer progression. THC offers some promise, but we have a long way to go before we know what its potential is.”
Targeted Release of Oncolytic Measles Virus Searches and Destroys Orthotopic Human Gliomas in Mice While Being Protected Against a Neutralizing Immune Response
Researchers in Germany reported that they have hidden vaccine-grade measles virus inside artificially generated blood cells in order to devise a search-and-destroy therapy for human gliomas that can’t be “seen” by the immune system. Dr. Jiwu Wei of the University Children’s Hospital, Ulm, Germany, and colleagues used human blood outgrowth endothelial cells (BOECs), readily expandable from human peripheral blood, as cellular carriers. The BOECs were infected ex vivo with the measles virus MV-Edm.
After systemic and peritumoral injection into mice with orthotopic human gliomas, the BOECs specifically searched U87 glioma cells, navigating through normal brain tissue, without being significantly sequestered into normal tissues. Migration of the BOECs was mediated by placental growth factor (PGF) and VEGF. Some BOECs integrated into tumor vessels. Release at the glioma of the viruses led to focal cytopathic infection of the glioma cells that decreased the glioma size and prolonged overall survival of the mice. In vitro, the viruses efficiently infected and killed the U87 glioma cells, even in the presence of natural immune serum that completely ablated the infection. The investigators concluded that BOECs infected with oncolytic measles virus resist cell death and protect the measles virus against immunological neutralization. They provide the firsts evidence that MV-Edm in tumor-searching and protective cellular vehicles such as BOECs may constitute a promising new treatment modality for gliomas.
Dr. Christian Beltinger, an Associate Professor at University Children’s Hospital in Ulm, was one of the investigators of the study. He explained, “In an immune-competent patient, the immune system will fight the virus, and most adults are immune against measles since they have been vaccinated against the disease in childhood or have had measles, Although cancer patients are immune-compromised by their disease or because of therapy, they still may mount a sufficient attack against vaccine measles virus.
Dr. Beltinger added that the BOECs “do not naturally occur in the blood, but they are derived from endothelial progenitor cells, rare cells that are produced in the bone marrow and shed into the blood. Tumors need vessels to grow; hence, they recruit these blood progenitor cells. That makes them home to the tumors. BOECs have been used for other gene therapeutic approaches, such as for hemophilia, but this is the first time they have been adapted to carry vaccine measles virus. While these modified blood cells carrying vaccine measles virus look like a promising novel therapy for gliomas, it is still a preclinical experimental approach. Potentially it could be used on most malignant gliomas, including glioblastomas, because the targeting of the virus can be genetically modified.
These novel therapeutic approaches represent the latest advances in targeted cancer therapy. Targeted cancer therapies may one day provide clinicians with a better means of custom-tailoring cancer treatment. Eventually, treatments may be individualized based on unique sets of molecular targets.
1. Sarkar D, Lebedeva I, Su Z-Z, Park ES, Vozhilla N, Fisher PB. Eradication of resistant prostate cancer by a novel gene therapy
approach. Proc Am Assoc Cancer Res. April 14-18, 2007; Los Angeles, CA. Abstract 4182.
2. Kajiwara T, Takeuchi T, Ueki T, et al. Effect of Bcl-2 overexpression in human prostate cancer cells in vitro and in vivo. Int J Urol.
3. Batchelor TT, Duda DG, Di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor
vasculature and alleviates edema in glioblastoma patients. Proc Am Assoc Cancer Res. April 14-18, 2007; Los Angeles, CA.
4. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58-62.
5. Ilhan N, Ilhan N, Deveci F. Functional significance of vascular endothelial growth factor and its receptor (receptor-1) in various lung
cancer types. Clin Biochem. 2004;37:840-845.
6. Caffarel MM, Sarrio D, Palacios J, Guzman M, Sanchez C. Δ9-tetrahydrocannabinol inhibits cell cycle progression in human
breast cancer cells through Cdc2 regulation. Cancer Res. 2006;66:6615-6621.
7. Jia W, Heqde VL, Singh NP, et al. Δ9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by
translocation of Bad to mitochondria. Mol Cancer Res. 2006;4:549-562.
8. Preet A, Ganju RK, Groopman JE. d-9-tetrahydrocannabinol inhibits growth and metastasis of lung cancer. Proc Am Assoc
Cancer Res. April 14-18, 2007; Los Angeles, CA. Abstract 4749.
9. Arsham AM, Plas DR, Thompson CB, Simon CB. Akt and hypoxia-inducible factor-1 independently enhance tumor growth and
angiogenesis. Cancer Res. 2004;64:3500-3507.
10. Wei J, Wahl J, Nakamura T, Stiller D, Debatin K-M, Beltinger C. Targeted release of oncolytic measles virus by blood outgrowth
endothelial cells in situ inhibits orthotopic gliomas. Proc Am Assoc Cancer Res. April 14-18, 2007; Los Angeles, CA. Abstract