Emerging and Experimental Approaches in the
Treatment of Hormone-Refractory Prostate Cancer
Last Revised January 6, 1996
[Note: considerable development has been made in trials and new therapies since this was written, that may change the information.]
Introduction |
Warning to patients |
Gene therapy |
Apoptosis-based treatments |
Immunotherapies and monoclonal antibodies |
Growth arrest and differentiation therapies |
Interference with cell signaling pathways |
New approaches take time
Introduction
The range of experimental and investigational therapies for
hormone-refractory and earlier stages of prostate cancer is almost
staggering. PSA testing has vastly increased awareness and diagnosis of this
disease, and increased longevity has inevitably impacted the numbers of
men for whom clinically significant prostate cancer will be a problem in
their old age. There are therefore multiple motivations for the development
of innovative new forms of therapy.
Because there are almost no truly effective forms of therapy available to the
patient who fails hormone therapy, a great deal of the ongoing research is
focused,
in experimental settings, upon very late-stage patients. It should be noted
immediately, however, that the true value of some of these forms of
therapy may subsequently be found to be in earlier stages of prostate cancer.
The information which will be provided in this section on emerging and
experimental therapies is not exclusive or comprehensive, nor is
it intended to be so. The careful user of The Prostate Cancer InfoLink will
find many references to other forms of emerging and experimental therapies in other
sections. For example:
- Click here to find information on the
investigational agent suramin in the treatment of hormone-refractory
disease (and potentially in hormone-naive patients with stage M+ disease).
- Click here to gain information on the
possible role of finasteride in the prevention of prostate cancer.
- Click here to read through the
section on chemotherapy
of hormone-refractory prostate cancer, in which there are many forms of
therapy currently under investigation, some of which are increasingly
beginning to show promise.
- Click here to find information
on the potential use of somastatin analogs such as octreotide acetate in
the treatment of hormone-refractory disease.
This section will be continuously updated as information on new forms of therapy
for hormone-refractory disease either become possible or are shown to succeed or
fail. Patients should recognize, however, that if they are in search of
investigational new forms of therapy for late-stage prostate cancer, The
Prostate Cancer InfoLink will not always have every piece of the most recent
information. They should always consult with their personal physicians and
use other resources in searching for additional data.
Warning to patients
Patients should be extremely cautious if asked to become involved with certain
types of experimental and emerging therapy for the treatment of prostate cancer.
Unfortunately there are individuals and organizations which prey on the very
sick by offering unproven "investigational" therapies outside the normal
processes designed to gain approval for new forms of treatment. Patients are
advised that there are some relatively simple steps that they can take in order
to ensure the validity of a clinical research program:
- First, they should ascertain the qualifications of the clinician to carry out
such research by talking with a physician whom they know and trust.
- Second, they should ask if there is a written protocol
according to which the study is being conducted.
- Third, they should be aware that such studies are usually carried out under
research grants from the government, from private companies, or from other
independent resources. Thus, treatment is often free or at least there
is no charge for the investigational agents or for the tests needed to evaluate
the benefit of those agents.
- Fourth, patients should be extremely suspicious of supposed investigational
therapies for which they are asked to pay large sums of money in advance of
treatment.
- Finally, all reputable US clinical research institutions are required to
have human research protocols conducted only with the approval of an "institutional
review board" or IRB. If there is any doubt about the validity of a
clinical study, ask to see the documentation of IRB approval and the written
study protocol.
On the other end of the scale, it should also be pointed out that there are
literally thousands of clinical investigators and research groups world wide
who are trying to find new forms of therapy for prostate cancer and who
desperately need patients to enroll into clinical trials of investigational
and experimental agents. The Prostate Cancer InfoLink strongly encourages
patients to participate in well organized and properly conducted clinical
trials of new forms of therapy.
Gene therapy for prostate cancer
The manipulation of the processes of human cell division and growth in order
to increase, decrease, or otherwise fundamentally change the biochemistry of
individual patients has come to be known as "gene therapy." This is probably
an unfortunate term, because in many cases one does not actually change
the patient's genes at all; rather, one attempts to amplify or reduce the
activity of a particular biological process by manipulating the control
systems which switch certain processes on and off in the body. Be that as
it may, "gene therapy" is considered to hold enormous potential
in the treatment of hundreds of different human disorders, of which cancer
is considered to be one of the most interesting.
One of the specific applications of gene therapy to prostate cancer currently
involves attempts to immunize patients with transformed prostate tumor
cells so as to induce immunologic activity against the tumor which is
already present in the body.
The general basis of all forms of gene therapy for prostate cancer require
tumor cells to be removed from the patient, transformation of those cells using
radiation, genetic engineering techniques, and concomitant cytokines [such as
granulocyte-macrophage colony stimulating factor (GM-CSF) or an interleukin].
The transformed cells are then returned to the patient, where it is hoped that
they will induce a new form of immunobiological response to the cancer that is
already present such that the patient's modified immune system is now capable of
"fighting off" the cancer in the same way as we fight off a cold or an
infection.
The details of all of the differing forms of gene therapy under investigation
for prostate cancer would require an entire web site on their own, and it
simply is not possible to go into all of these differing research projects on
The Prostate Cancer InfoLink at this time. The important thing for patients to
understand at present is that all forms of gene therapy are highly
speculative at present. It would be a major surprise to most researchers
and clinicians if we were to be able to bring an effective form of gene therapy
for prostate cancer out of research and into general practice within the
next 5 or perhaps even 10 years. Even in those diseases in which gene therapy
research has been ongoing for many years (e.g., cystic fibrosis and renal cell
carcinoma), success to date has been very limited, and in the case of cystic
fibrosis the disease should be completely curable if we could just find a way to
teach the patient's bodies to make one missing enzyme!
The Prostate Cancer InfoLink sincerely considers that in time we will learn how to
increase our control over the body's normal immunological function through immunogenetic
manipulation so as to be able to protect patients from many cancers -- particularly
a disease like prostate cancer because it develops so slowly over time. However,
we also consider that patients' expectations must be tempered by the realities
of the scientific and clinical research processes. Major advances take time.
This has been exemplified most recently by our failure to find truly effective
forms of long-term therapy for AIDS, despite billions of dollars worth of research
and countless different attempts to seek different approaches to the problem.
Apoptosis-based treatments
"Apoptosis" is the process of deliberate induction of natural cell death. In the
normal human body, cells die all of the time, and (with the exception of certain very highly
specialized cells such as nerve cells) our bodies are in a constant state of
gradual renewal. The process of constant renewal is a controlled one. Thus,
if we could manage to understand the process of control of the growth and
death of prostate cancer cells, we might be able to find ways to deliberately induce
programmed death of prostate cancer cells in the body.
As it happens, the induction of programmed call death has been exceptionally thoroughly
studied in prostate cells following hormonal therapy. Indeed, there is some evidence
that the potential benefits of neoadjuvant hormonal therapy prior to
radiation therapy or surgery are based on the induction of apoptosis.
Precisely how the apoptotic response is stimulated is still unknown. However, it
is now clear that many different types of process can induce this response -- at
least in the laboratory. These processes appear to include:
- Hormonal ablation (with combinations of antiandrogens, LHRH agonists, and
perhaps 5-alpha-reductase inhibitors)
- Antiestrogen therapy
- Treatment with at least some of the so-called "transforming growth
factors" (e.g., TGF beta)
- Increases in the level of intracellular calcium.
It is apparent that induction of apoptosis involves profound biochemical changes
at the genetic level. For example, we already know that previously unknown genes
are "switched on" or activated during the induction of apoptosis. On the other
hand, previously known enzymes are also important. It is expected that it will
take some time before we have a sufficient understanding of the induction of apoptosis
to be able to design new pharmaceuticals which are specific to initiation
of programmed prostate cancer cell death. However, this is one more
promising avenue of current research.
Immunotherapies and monoclonal antibodies
For some time, researchers have been attempting to find ways to treat various
cancers by using carefully targeted immunotherapeutic agents, i.e., agents which
will (like the so-called magic bullets envisaged for the treatment of
infectious diseases in certain organ systems) travel to and then attach to
the specific sites where prostate cancer cells need to be destroyed before
activating the destructive portion of the agent.
One way in which researchers have been attempting to do this is through the
development of monoclonal antibodies -- clones of cells which have a specific
affinity for prostate cancer cells. By attaching molecules which will kill
(or at least inhibit further growth of) prostate cancer cells to monoclonal
antibodies which will seek out and attach to those prostate cancer cells, it
should (theoretically) be possible to produce carefully designed and targeted
therapeutic agents.
Of course theory and reality are not necessarily the same thing at all, and
while there has been extensive progress in this area, we do not yet have available
any actual therapeutic agents which work on this principle for the treatment
of cancer. There are, however, some interesting signs that we are getting closer:
- In the first place, we expect shortly to see the approval of a monoclonal
antibody-based prognostic marker which will use this type of procedure to
deliver the radio-isotope indium-111 to sites of micrometastatic prostate
cancer, thus allowing imaging of these sites. In other words, the theory does
have practical application in prostate cancer.
- Secondly, the technology has now been used to develop therapeutic agents
used in the treatment of other disorders, and therapeutic products based on
this technology can be expected to become more widespread in the next decade.
A completely different approach to the use of immunotherapy for prostate cancer
is based on the concept that certain normal prostate cancer proteins (and
particularly mutant p53 proteins) may be used as targets for what are known as
induced cytotoxic T cells. Because p53 mutations are apparently common in
patients with advanced prostate cancer, this may represent another potential
approach to the effective treatment of later stages of prostate cancer.
Growth arrest and differentiation therapies
Differentiation therapy is a form of treatment that has previously been applied to some other forms
of cancer with varying degrees of success. However, attempts to apply this form of therapy to
prostate cancer are comparatively recent.
The basis of differentiation therapy requires an appreciation of the ways in
which cells and classes of cells mature over time. The more a cell becomes
specialized (differentiated), the more likely it is that one may be able to
tempt that cell into a state of growth arrest and thus induce what is known as
"terminal differentiation." In the case of prostate cancer cells, there is
a tendency to exhibit neuroendocrine differentiation. In other words, at least
some types of
prostate cancer cells may be thought of as being a misplaced attempt to
develop into neuroendocrine cells. While we now know that the presence of
these types of cells in prostate cancer patients is not a good sign, we
also know that differentiation therapy may present an option in the treatment of
some patients with this type of advanced prostate cancer.
The development of therapies which may be usable to treat this form of
prostate cancer is in a very early stage. However, it would appear that
there are a number of different agents which can be investigated:
- Analogs of cyclic adenosine monophosphate (cAMP) appear to have effects
on enzymes relevant to the growth of prostate cancer cells.
- In laboratory studies, phenyl acetate appears to be able to convert
malignant prostate cancer cells into a non-malignant state.
- A synthetic agent known as fenretinide also appears to be able to convert
malignant cancer cell lines to a non-malignant state in laboratory tests.
- Derivatives of vitamin D appear to have the ability to affect the growth
of certain types of prostate cancer cell lines.
Patients must appreciate that success in laboratory and very early stage clinical studies
of this type do not necessarily imply that new forms of therapy will result.
All too often, promising therapies fall by the wayside because the laboratory
results cannot be reproduced in real patients and because the adverse events
which may accompany the desired clinical effects are simply too dangerous
for the new methods to be clinically useful. It may be some time before any
of these forms of therapy can be shown to be both effective and safe on even
the most limited scale.
Interference with cell signaling
pathways
All cell systems use complex biochemical signaling systems in order to
tell each group of cells how to behave under specific circumstances. We
have long suspected that many illnesses are the consequence of disturbances
in these cell signaling pathways, and we already know that the clinical
use of certain cell signaling biochemicals (e.g., granulocyte colony
stimulating factor or G-CSF, which is commercially available as Neupogen)
can be used to alter certain effects commonly observed in patients receiving
some types of chemotherapy. (Specifically, G-CSF is commonly used in
combination with certain types of chemotherapy in order to prevent a
serious side effect of chemotherapy known as neutropenia.)
There are reasons to believe that just as we may be able to augment certain
effects in the human body by introduction of cell signaling biochemicals
like G-CSF, we may also be able to disrupt other pathways. These potential
methods of treatment for prostate cancer are highly experimental at present.
They involve the possibility of using certain types of protein and
peptide to block or otherwise interfere with a whole range of possible
cell signaling pathways and systems.
New approaches take time
The existence of potential new approaches to the treatment of late-stage prostate cancer
may all too often be of very little help to patients who already have hormone-refractory
disease. The Prostate Cancer InfoLink appreciates that the patient with
hormone-refractory prostate cancer is seeking help now, not at some
ill-defined and perhaps undefinable date in the future.
There is nothing more frustrating to a young patient than knowing that
there may be some new form of therapy "just a few years away." Sadly, this
is one of the consequences of the huge strides we have made in the treatment
of disease since the late 19th Century. A hundred years ago, we would never
have been able to hold out the sorts of hope for the future that we can today
when it comes to the treatment of prostate cancer. On the other hand,
nature is infinitely adaptable. For every disease we succeed in conquering,
a new disease comes along. As we have extended the human lifespan, we have
introduced risks from diseases that barely bothered our ancestors because
few people lived long enough to contract these disorders:
Alzheimer's disease, prostate cancer, multiple myeloma, even benign prostatic
hyperplasia are disorders which perhaps we have to realize that we are lucky
to live long enough to contract, as compared to the shorter and less
comfortable lives of our predecessors.
It will take time to find better treatments for prostate cancer. Every patient
has the ability to contribute toward the development of new treatments through
the way in which he shares knowledge with his family, his physicians, and
perhaps participates in clinical trials of new forms of therapy.
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