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
Angiogenesis
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
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.
Immune tolerance
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.
Signal transduction
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.
Last Edited: Dec 07, 2007 3:29 PM
