Beyond Surgery, Radiation and Chemotherapy What’s New in Cancer Therapy?
Surgery, chemotherapy and radiation are not enough to treat tumors with a high capacity for metastasis, and only minimal increases in survival seem to be forthcoming with further research in these fields. Classic cancer therapies have always exploited very large or "macro" differences between cancer and normal cells-differences in proliferative rates, DNA synthesis rates, and inefficient repair of damage induced by therapy. This approach has led to very good responses in a few rapidly dividing tumors with relative stability in their genomic information. Most specifically this has led to cures in the human field in non-Hodgkin’s lymphosarcoma and germ cell tumors, and our animal patients can also be occasionally cured of lymphosarcoma, but other metastatic diseases have not had the same success.
The age of more targeted therapeutics has come. These therapies will only be possible with a thorough basic understanding of the neoplasia we are trying to treat, advances in chemistry and biotechnology, and working towards selectivity to achieve a high therapeutic index. Many possible novel targets exist- most importantly Tumor induced angiogenesis Evasion of apoptosis by cancer cells Immune tolerance of cancer cells Signal transduction within the cancer cells Tissue invasion and metastasis of cancer cells Cell Cycle dysregulation
Tumor growth is dependent on vascular growth and it is generally accepted that a tumor cannot grow >1mm3 without neovascularization. Vascular supply is necessary for all tissues for delivery of nutrients, growth factors, hormones, and oxygen, along with the removal of wastes and toxins. Vascular supply is also often how the immune system can survey or gain access to the tissues of the body. Tumor vasculature is molecularly distinct from normal vasculature and the tumor endothelium represents a valuable target for anti-cancer therapy.
There are basically two ways tumor blood vessels can be targeted. The first is to inhibit the tumor from initiating the angiogenic process. This can be achieved theoretically by interfering with delivery or export of angiogenic stimuli, using antibodies that inhibit or inactivate angiogenic factors after their release, or using Inhibitors of receptor activity, tumor invasion or endothelial cell proliferation. Inhibiting the formation of neo-vascularization will only really help in the prevention of tumor metastasis after definitive therapy against the tumor has been used, or for stabilization of tumor size. They must be given continuously and they will never cause regression of tumor. Preferentially destroying established tumor blood vasculature would bring about more profound effects in established tumors. Agents known as vascular disrupting agents (VDA’s) are designed to induce rapid and selective vascular shutdown in tumors. They are given only intermittently. Two categories include biologics and small molecules. Biologics are antibodies or peptides that deliver toxins and pro-coagulant and pro-apoptotic effectors to tumor endothelium. VEGF (vascular endothelial growth factor) is often targeted as the determinant we want our antibody to find, but there are many others currently being studied as well. Small molecules are agents that exploit known differences between tumor and normal endothelium to induce severe vascular dysfunction. No drugs have yet cleared the FDA that target tumor vasculature but clinical trials alone and in conjunction with chemotherapy or radiation therapy are ongoing. Thalidomide is known to be a theoretical anti-angiogenic drug and this is partly why it caused the birth defects it did.
Apoptosis equals programmed cell death. Cells do not live forever (or else we would all be immortal) and they must die at an appropriate time to allow for the normal function of the entire individual. Evasion of apoptosis is an obvious necessity for continued tumor growth. It is not yet known if this will be a valid cancer therapy site but researchers continue to be hopeful. Apoptosis is activated by two pathways, intrinsic (in the mitochondria or the cells power house), and extrinsic (via receptors on the outside of the cell). The intrinsic pathway is affected by conventional therapies but, mutations in the pathway commonly occur, rendering tumors resistant to conventional therapies. The extrinsic (receptors) pathway may provide a target for novel therapies that can circumvent resistance problems. The TNFa (tumor necrosis factor alpha) receptor family- most specifically the TRAIL receptor family is receiving the most attention.
Tumors avoid the immune system probably via a variety of mechanisms- but above all they are recognized as "self" by the body. They may be functioning abnormally but they are still genetically a part of the body. They are not looked at as foreign like a virus, bacteria, another individuals body part, or things the body tries to destroy. Immune therapy is an attempt to get the immune system to recognize a tumor as something it should be trying to destroy. Non- specific immune modulators include substances such as intact bacteria, or bacterial cell components, Acemannan ( a veterinary drug often touted for it’s ability to help in the treatment of fibrosarcomas) , Vitamins/minerals, IL-2 (interleukin 2), and IFN-a (interferon alpha). A variety of chemical agents have effects on the immune system as well. Levamisole ( a large animal deworming product) , COX-2 inhibitors (cyclo-oygenase inhibitors which are drugs like aspirin, piroxicam, rimadyl, deramaxx etc), and Cimetidine have all been used as non-specific immune stimulants and the COX-2 inhibitors have been shown to do more than just immune stimulation.
More specific methods of using the immune system include the use of monoclonal antibodies (a purified form of antibodies which recognize cancer cells) and cancer vaccines. Monoclonal antibodies specific for an individuals tumor are not easy to produce so most research these days uses anti-bodies against a specific target like VEGF or an RTK (see below). Vaccines are no longer just a chunk of an individuals tumor injected back in to the individual. Such vaccines are expensive to produce and often not effective because of the failure to recognize "self". Tumor vaccines these days are genetically engineered antigen sources designed to stimulate an immune response against an established tumor. The antigen source, or target, these days is often cancer DNA. The best vaccines now seem to combine a similar gene from a different species (mouse for humans, human for mouse, or mouse or human for dog). This increases the antigenicity (ability of the body to respond to the vaccine) of the vaccine and helps circumvent the problem of tolerance to self. Also other agents are frequently incorporated to increase immune reactivity to tumor antigens. These agents include: cytokines or cell communicators (GM-CSF, IFN-g , IL-2); molecules, cells or cell lysates; other adjuvants or haptens. Vaccine protocols often vary in administration schedules, injection procedures, and routes of administration.
Aberrant signal transduction elements occur in most cancers. Signal transduction refers to the means by which cells are triggered either via external or internal influences to go about their normal daily functions. In most cancer cells the pathways are not functioning properly. Mutated signal proteins are often oncogenic or tumor causing. Consitutive activation of signaling elements (or constantly turned on) can confer autonomy to a cell population. In other words, the cells no longer carry about their normal daily functions; they become a growing cancer population because their normal information pathways aren’t functioning properly. Changes in these signal transduction elements have been linked to increased potential for proliferation, invasion, and metastasis and increased angiogenesis. For the patient this means decreased survival, poor response to standard chemotherapy, and an overall poor prognosis.
Receptor tyrosine kinases (RTKs) are the main mediators of the signaling network that transmit extracellular signals into the cell and control cellular differentiation and proliferation. Overexpression of RTK proteins, or functional alterations caused by mutations in the corresponding genes, or abnormal stimulation by autocrine growth factor loops contribute to constitutive RTK signaling. Constitutive signaling results in poorly regulated cell growth and ultimately- cancer. Sixty different kinases in 16 different families are known to exist. The receptors show homology particularly in the protien portion which resideds inside the cell. Knowing the mechanism of an individual RTK can lead to rationale anti-RTK drug development. Primary targeted families include: EGFR-ErbB family (epidermal growth factor receptor), C-Kit (proto-oncogene coding for an RTK), and VEGFR‘s (vascular endothelial growth factor receptor) but the list is far larger. Mechanisms by which these receptors can be inhibited are varied and research is constantly ongoing.
The primary drugs you may have heard about in this class of drugs are Herceptin- an antibody to the HER2/neu (an EGFR on many breast cancers)- which plays a significant role these days in the treatment of breast cancer for women with HER-2/neu positive tumors. Also, Gleevac is a tyrosine kinase inhibitor effective against chronic myelogenous leukemia and small cell lung cancer. An up and coming drug for non-small cell lung cancer is Iressa- also a tyrosine kinase inhibitor. It is currently in use in Japan but not in the US.
Tissue invasion and metastasis of cancer cells
Most human cancer patients die of metastatic disease. If one could simply stop tumors from spreading to other sites it would make cancer treatment so much easier. To metastasize, cancer cells must erode into the blood stream or lymphatic channels in the first place, and eventually they must erode back out into some other tissue. Inhibition of this ability to invade across these stromal tissues could stop tumor metastasis. Many research groups have been, and are examining this area of anti-cancer therapy.
We are currently working on some projects right here at WSU examining the genetics of metastasis and looking at dogs with naturally occurring tumors to see if they might serve as model for a particular mechanism seen in human cancers. The hopeful outcome of this effort is to have an animal model of a metastasis pathway identified in humans, and ultimately to develop therapy aimed against the pathway with clinical trials occurring first in dogs.
What’s new in veterinary cancer therapy?
The glorious new world of anti-cancer therapies in humans is of limited availability in veterinary medicine. The more specific the therapies become the less we will be able to apply them to our patients unless the targets are identical- which some will be. Our attempts at immune modulation are primarily aimed at this time at treating melanomas and osteosarcomas. Administration of over the counter cimetidine (Tagamet) for stimulation of the immune system through the suppression of T-suppressor cells is probably most helpful with melanomas. It may not help as much as we would like- but it won’t hurt either. Vaccine trials are underway with dog melanomas and osteosarcomas although most are associated with a specific institution.
Tyrosine kinase inhibitors are beginning to be explored in the treatment of canine mast cell tumors. The c-kit proto-oncogene has been well studied in canine mast cells thanks to Dr. Cheryl London, and the presence of molecular alterations in the gene in mast cell tumors has been linked to prognosis. The protein product of the gene is a receptor tyrosine kinase- Kit. Clinical trials are underway with receptor tyrosine kinase inhibitors but as of now no product is commercially available. Most likely Mast cell tumors are not the only class of tumors where tyrosine kinase inhibitors could have a role in therapy, but they are the only tumor to date where the basic biology of the tumor has been so well worked out. And that is a requirement for the modern development of rational targeted therapies.
VEGF has been measured in several dog tumor situations but has not been targeted in any clinical trial yet published.
An exciting and simple treatment of cancer is the class of drugs previously known as NSAID’s but now more commonly referred to as COX-1 and COX-2 inhibitors. Nearly any NSAID has the ability to benefit any cancer patient through immune modulatory, pro-apoptotic, and anti-angiogenic effects, not to mention pain control. These drugs also act through suppression of cyclo-oxygenase (COX) 2. Many tumors, predominately carcinomas, have upregulated COX-2 and blocking the enzyme can help with tumor control. Piroxicam has been the drug most researched clinically, but theoretically any of the newer NSAID’s with greater specificity for COX-2 could give equal or better effects. Never underestimate the power of these drugs. The use of COX-2 inhibitors is one of the hottest areas of cancer research going at the moment and the whole thing started with an accidental discovery in dogs.