The problem of cancer
Patients that present with metastatic disease or those who develop metastases after successful management of the primary tumor carry a universally grave prognosis. Conventional therapeutic options are poorly effective in most cases. As such novel treatments for patients with a risk for metastasis or for those who have already developed metastases are needed. Our understanding of the biology of metastasis has expanded in recent years and is now shedding light on novel treatment strategies for patients with gross metastases and those with a high risk of metastatic recurrence.
The Biology of Metastases
In order for a cancer cell to successfully metastasize it must leave the site of the primary tumor, pass through the tumor basement membrane, and then through or between endothelial cells to enter the circulation (extravasation). While in the circulation tumor cells must be able to resist anoikis (programmed cell death associated with loss of cellular contact), evade immune recognition and physical stress, and eventually arrest at distant organs. At that distant site the cell must leave the circulation and survive in the hostile microenvironment of the foreign tissue site. This distant site may be the eventual target organ for metastasis or may be a temporary site. In either case the cancer cell is thought to lie dormant for a protracted period of time before moving to its final location. Following dormancy, the cells receive signals to proliferate, create new blood vessels (angiogenesis) or co-opt existing blood vessels and then successfully grow into a measurable metastatic tumor. It is likely that further progression is associated with the repetition of this process resulting in metastases from metastases.
New Treatments Based on an Improved Understanding of Biology
Through an improved understanding of the biology of cancer metastasis, novel treatment approaches are now commercially available, and others are in clinical trials. This session will summarize the newly available agents and the status of agents still in the development process. No matter how promising these treatments may be, it is predictable that cancer cells will be able to overcome each individual therapy. As such, it will be important to define how these novel treatments may best be used in combination with conventional chemotherapy agents and with other novel treatment agents. A discussion of specific novel treatments agents for cancer is presented with the relevant metastasis-associated process.
Dissolving the extracellular matrix is essential for cancer cells as they initiate the metastatic process within the primary tumor site and when cells leave the circulation at distant metastatic sites. This process of invasion is mediated by a series of enzymes including matrix metalloproteinases (MMP). Many commonly used veterinary drugs inhibit MMP activity (i.e., doxycycline); however, agents specifically designed to antagonize these enzymes have been developed and evaluated in both human and veterinary cancer patients. Most clinical trials, in human patients, using MMP inhibitors have not been successful. A failure to define optimally effective doses and treatment schedules, as well as unexpected toxicities related to these MMP inhibitors may in part explain their failures as drugs. Interestingly, at doses well below those used in human clinical trials, modest improvements in outcome were seen in selected dogs with lymphoma entered to a randomized, placebo blinded trial with a selective MMP inhibitor in combination with conventional chemotherapy. The improvement was most evident in older dogs and dogs with the highest pre-treatment MMP levels (Personal communication G. Ogilvie).
Evade Immune Surveillance
The belief that the immune system may play a role in the treatment of cancer has been held for over 100 years. Coley, a surgeon in the early 1900s, observed the spontaneous regression of bulky tumors in women following bacterial sepsis. His belief that the fever associated with sepsis was responsible for regression of the tumors lead him to administer mixtures of bacteria to patients in the hopes of re-creating fever and resultant tumor regression. These bacterial mixtures, referred to as Coley's toxins, were the first documented attempts at cancer immunotherapy. Since the days of Coley, considerable progress in our understanding of the immune response (and lack of immune response) against cancer has emerged. This understanding may be summarized in the following generalizations:
Cancers differ in their sensitivity to immune recognition and destruction (immunogenicity)
The determinants for immune recognition of cancers are specific to each cancer type
Cancers evade immune recognition by many different mechanisms
The cell-mediated immune response is important in generating immune recognition of the cancer
Cancer immunotherapy is likely to be most effective against small tumor burdens
This understanding has lead to several promising strategies that use the immune system to first detect and then destroy cancer cells. Approaches to immunotherapy include the following:
Non-specific Immunotherapy--where bacterial agents (e.g., BCG, Corynebacterium Parvum), natural products (Acemannan), synthetic compounds (Muramyl tripeptide), chemical agents, and others, are used to stimulate an immune response. This approach is similar to that of Coley, and is referred to as non-specific because the target for immune recognition in the cancer is not known. The most extensively studied form of non-specific immunotherapy in veterinary oncology is muramyl tripeptide (MTP). In randomized, controlled, and placebo-blinded trials, MacEwen et al have demonstrated the activity of MTP against canine osteosarcoma and canine hemangiosarcoma. Treatment of dogs with osteosarcoma or hemangiosarcoma using MTP plus chemotherapy resulted in significantly longer survival times compared to chemotherapy alone. There has been a renewed commercial interest in the development of MTP by IDM, Inc., who is considering the development of MTP for pediatric osteosarcoma patients.
Specific Immunotherapy--attempts to generate a specific immune response against a known or unknown tumor antigen (target). A tumor vaccine is the most common form of specific immunotherapy. Our understanding of the immune response against cancer suggests that the most effective tumor vaccines will stimulate cell-mediated responses against cancer. Clinical trials using a number of vaccination approaches are currently ongoing at several sites in the United States for dogs with melanoma, osteosarcoma, and hemangiosarcoma. In some cases, these treatment options do not require travel to the sponsoring institution. More information about these clinical trials can be found at www.vetcancersociety.org.
Adoptive Immunotherapy--refers to the administration of parts of the immune system to a patient. Monoclonal antibodies raised against cancers represent adoptive humoral immunotherapy. Advances in the design of monoclonal antibodies to prevent immune reactions against the antibody and to improve antigen recognition have raised the potential value of this type of therapy. The land-mark approval of Herceptin®, an antibody that binds the Her2/neu gene product, to treat breast cancer in women is evidence of the progress that has been made in this field. Since the approval of Herceptin, a series of antibody-based therapies have become available for the treatment of cancer in human patients (e.g., Avastin, Erbitux, Rituxin). These treatment approaches have received considerable press and as such, interest from pet owners; however, humanized monoclonal antibodies are not likely to have wide application in the treatment of canine or feline cancers since the development of neutralizing antibodies against these human proteins is likely to occur. Future development of smaller fragments of antibodies, peptide antibodies, may have greater transferability to veterinary patients.
Cytokine Immunotherapy--refers to the administration of products of the immune system (cytokines) to stimulate or direct anti-tumor immune responses. Cytokines are released by leukocytes and function in the activation and regulation of the immune response. Cytokines, such as interleukin-2 (IL-2), have been used to induce significant anti-tumor immune responses and objective tumor responses in dogs with osteosarcoma. We have shown in a small number of dogs with pulmonary metastasis from appendicular osteosarcoma (4/16), complete regression of metastases after the inhalation IL-2. Interleukin-2 is commercially available through most large drug distributors. It is not likely that cytokine therapy will become a single cancer treatment, rather it is more likely that it will become part of another immunotherapeutic approach (i.e., used as a cancer vaccine adjuvant). Information on the delivery of aerosols of IL-2 are available at www.animalcancerinstitute.com.
Survival at Distant Sites
The ability of cancer cells to survive in distant "foreign" tissues immediately after arrest or while cancer cells are in a dormant state is a hallmark of successful metastasis. For most metastatic cancers, this ability to survive is in part regulated by internal genetic cues, but also by signals received from the microenvironment (growth factors). A number of small molecules that inhibit signal transduction from growth factor receptors have been developed as cancer agents. Many of these agents may have a role in treating metastases through the disruption of critical survival signals provided by these growth factor receptors. In work from London et al, a small molecule inhibitor (SU11654) of the split tyrosine kinase receptor family was found to be active in a number of canine cancers, including mast cell tumors, metastatic sarcoma, and mammary carcinoma.
The split tyrosine kinase receptors that are inhibited by SU11654 have a diversity of biological effects. As such, their inhibition may not be limited to preventing survival and may be the result of the inhibition of many steps in the metastatic cascade. As a class, small molecular inhibitors of tyrosine kinase receptors represent one of the most promising types of novel therapies for cancer and cancer metastases. Clinical trials using these agents are underway at several veterinary referral centers and veterinary teaching hospitals across the United States.
Angiogenesis describes the generation or recruitment of new blood vessels. It appears that new blood vessel development is essential for tumor cells to grow and metastasize. The new blood vessels may be created by the tumor or may be recruited from the surrounding normal tissues. If new blood vessel formation or recruitment can be inhibited, a tumor cannot progress and may cause established tumors to regress. Therapies that are directed against blood vessels and not tumor cells are likely to be active against a wide spectrum of cancers. Biological differences between tumor associated endothelial cells and normal endothelial cells have become apparent. This has lead to several novel therapeutic agents that either prevent new blood vessel formation or survival (antiangiogenic agents), or specifically target existing tumor-associated blood vessels (vascular targeting agents). Recent studies using antiangiogenic peptides of thrombospondin-I (TSP-I) have demonstrated surprising objective regressions of metastatic cancers in dogs with a variety of histologies and have significantly extended remission duration in dogs with lymphoma when combined with chemotherapy (demonstrated in a randomized controlled trial). Trials with TSP-I peptides in dogs are underway at several sites across the United States.
Progress that has been made in our understanding of the basic biology of cancer has uncovered several opportunities for the treatment of cancer. The improved knowledge of cancer biology has allowed differences between cancer cells and normal cells to be identified and has uncovered important interactions that occur between cancer cells and the host. The cancer treatment strategies discussed above specifically target cancer, and as such are less likely to result in the toxicities that are associated with conventional cancer therapy. Effective and non-toxic cancer therapy is therefore the goal. In the very near future, we can expect these novel treatments to be used in conjunction with conventional cancer treatment modalities (surgery, radiation therapy, and chemotherapy) in the management of our veterinary cancer patients.