In medicine it has long been the
rule that the cure should fit the ailment.The diagnosis of disease has come a long way from the first systematic
attempts by Hippocrates and others to determine the correct treatment based
upon observing the disturbance of the balance among four humors (yellow bile,
black bile, phlegm, and blood).From
these first steps to codify and attribute a specific cause to a disease, a
variety of diagnostic tools have been developed and employed, including
standard clinical findings (body temperature, blood pressure, pulse, etc.),
diagnostic imaging (X-ray, CAT
scan, MRI)and laboratory tests (blood glucose, liver
enzymes, blood gases).The increasing
sophistication and power of these diagnostic tools has been directed toward
establishing the manifestations of a disease in a patient with a view toward
determining the correct means of treating that individual.William Osler, the 19th century
Canadian physician who is often described as the Father of Modern Medicine,
said, “The good physician treats the disease; the great physician treats the
patient who has the disease”.The notion
that care of the individual should be directed toward the person, not the
disease, has reached the point that we have moved from diagnosis based upon the
four humors to molecular medicine, which seeks to select the proper treatment
based upon differences in the sequence and expression of particular genes,
comprised of permutations of four nucleotides.
The development of molecular
medicine has brought us to a different perspective on diagnosis and treatment
of diseases that integrates knowledge of the patient with the development and
utilization of new means of treatment.This view has been considered variously as personalized medicine,
targeted therapeutics, theranostics, companion diagnostics, as well as targeted
diagnostics.This integrated approach to
diagnosis and treatment has profound consequences with regard to basic
research, laboratory medicine, drug development, and routine clinical practice
where there is a growing body of treatments and tools available in an
atmosphere where demands for efficiency and economy are becoming ever more pressing.
It is worth considering the
underlying assumption that treatment of disease is dictated by diagnosis.It has long been appreciated that a set of
symptoms as experienced by the patient and observed by the physician may have
more than one cause.For example, an
infectious disease such as pneumonia can be caused by a large number of agents.One treatment may not be effective for all
patients if there are a variety of causes for the same constellation of
symptoms, clinical findings and lab results.In many such cases diagnostic techniques have often been developed to
determine the appropriate treatment for a particular infectious agent.A more telling problem is assumption that all
individuals will respond identically to the same treatments, or manifest the
same symptoms as part of the same disease process.It is often the case that even when the
etiology of a disease is the same, e.g.
HIV infection or even the current version of influenza, the course of the
disease will differ among members of the same population.As our understanding of human genetics, and
more specifically the particular subtle differences among us, has grown these
variations have become easier to observe and in some, cases, rationalize in a
way that can inform effective treatment and public health measures.
In a
sense, there has been a continuous process of refining diagnosis and treatment since
the recognition of the existence of specific microbes which cause infectious
diseases, or different genetic changes which underlie various cancers.As it has been recognized that particular
microbes respond to different antibiotics, or different tumors respond to
different chemotherapeutic regimens, the standard of care has generally
improved.Most recently, largely as a
result of advances in molecular diagnostic testing and knowledge, there has
been a dramatic shift in our knowledge of the subtle differences in etiological
agents, disease processes, and the differences among individuals which affect
treatment response.This knowledge of
the molecular basis of disease has had profound consequences upon the interface
between these diagnostic assays and the development of new drugs.
One
area where the consequences of molecular testing have had the greatest impact
is in the treatment of various cancers.A brief consideration of breast cancer serves to illustrate how there
has been a paradigm shift in how diagnosis and treatment are approached.In the simplest sense treatment of cancer
involves the elimination of the tumor cells with some combination of surgery
and chemotherapy.At the level of
pharmaceutical interventions, historically the drugs used generally worked by
targeting a particular characteristic of cancer cells.Most often, the ability of cancer cells to
grow more rapidly than most normal tissues led to the use of cytotoxic
treatments which preferentially kill tumor cells, while leaving most normal
cells relatively undisturbed.In
essence, the purpose of diagnosis was to identify the disease, while the
mechanism of treatment was to target a process characteristic of the disease
state.This approach did not involve any
knowledge of the particular biology of the tumor, let alone the individual
patient.The first instance where this
situation began to shift was with breast cancer.Knowledge of human physiology suggested that
breast tumors were likely to be dependent upon the same hormonal signals that
influence the normal proliferation of breast tissue.For this reason, it was not uncommon for women
diagnosed with breast cancer to have their ovaries surgically removed in order
to slow the growth of tumor cells that might be dependent on estrogen, the
hormone that drives proliferation of mammary glands.Having had the tumor removed, along with
normal tissue that could potentially promote the growth of residual cancer
cells, the patient was left to be treated with drugs to kill any growing cells
that might serve as a seed for recurrence of the cancer.
The
development of drugs, notably tamoxifen, which acted as anti-estrogens,
chemically preventing the action of estrogen, made it possible to treat
patients, without removal of normal tissue.The standards of care became long-term use of anti-estrogen therapy to
prevent recurrence of the tumor.At the
same time, techniques were introduced which allowed a pathologist examining
breast tissue samples to determine whether or not a specific patient’s tumor
was actively expressing estrogen receptors, the molecules on the surface of
breast cells that allow them to respond to estrogen.In this way the analysis of the tumor was
able to go beyond the question of whether or not it was a particular type of
breast cancer, to address the critical issue of whether or not a given tumor
expressed a potentially “druggable” target.This was the first instance of targeted diagnostics, an approach based
upon diagnosis and treatment being coordinated processes.The concept that effective treatment requires
knowledge of the presence and nature of a drug target in an individual patient
or their abnormal tissue has become an essential part of the drug development
process and medical care in recent years.
The
general category of targeted treatment includes personalized medicine which
recognizes that individuals may differ in specific ways that influence the
metabolism of various compounds.This
view has fueled the development of personalized genetics where specific and
characteristic changes in the genome are cataloged and related to response to
specific drugs, or a predisposition to the development of particular diseases.This area will not be discussed in any detail
here, as the focus of this paper is on how understanding of biological
molecules and metabolic pathways characteristic of disease processes influences
the drug development process, from target selection to the regulatory approval
process, and ultimately patient management.Human cancers result from a series of progressive changes in the
cellular genetic material and its expression.The alterations that are involved in a particular type of cancer often
differ among patients with microscopically (anatomically) indistinguishable
tumors, and provide a powerful example of how molecular biology, diagnostics,
and pharmaceutical research can work together to provide optimal patient care.
The recognition that there are
specific molecules whose expression is altered in some subset of patients with
a given disease, e.g. estrogen
receptor in the majority of breast cancers, suggested that these might serve as
suitable targets for drugs which specifically treat those patients.It seemed reasonable to expect that drugs that
have a target that is essential to the biology of a particular tumor would be less
likely to affect “normal” cells and tissues, and thus be better tolerated by
the patient.This is similar to the way
that antibiotics, such as penicillin, whose target molecules such as cell wall
structures are absent in human cells, have little in the way of side-effects in
most people.
The stratification of patients on
the basis of the presence or absence of a particular target molecule can also
serve as a way to avoid unnecessary treatment of patients who are unlikely to
be responsive.The consequences of this
for the development and utilization of drugs are rather profound.Individuals who are determined to likely be
non-responders, should benefit by avoiding unnecessary delays and side-effects
which could delay or compromise effective treatment.From the standpoint of a pharmaceutical
company, selection of sub-populations of patients that are likely to respond to
treatment increases the likelihood that a drug will be approved.That is, rather than a drug which is equivalent
to the current standard of care used for all patients, a smaller ready market
and approval can be found for a drug that is more efficacious in one group of
patients, however small.Ascertaining
the size of this population, i.e.,
thefrequency that the drug target is
present and distinctly expressed in a general population of patients, early in
the process of identifying druggable targets can provide essential information as
to which candidate drugs to move along the drug pipepline.
Herceptin, a drug used in the
treatment of breast cancer, is a good example of how such a selection process
might be designed and how it can serve to identify potential markets, in the
form of drug-responsive patients.It was
recognized that the amount of a cell surface protein, termed HER2/neu, is
increased a in a subgroup of breast cancer patients with a poor prognosis.That is, HER2 was recognized as a prognostic
marker, one that could be used in predicting the course of disease.Genentech recognized this possibility, and
developed monoclonal antibodies that targeted the HER2 protein.One of these came to be designated
Herceptin.The initial clinical trials
of Herceptin failed to show any specific effect when used on women with
metastatic breast cancer, though as expected the side effects were minimal
compared to the traditional anti-cancer drugs which caused nonspecific damage
to growing cells and tissues. Efficacy
was only demonstrated, and FDA approval only came, when patients were
stratified based upon whether or not they expressed increased amounts of the
HER2 protein.The approval for the use
of Herceptin required a companion diagnostic to establish that it would be used
only in those patients who might show some benefit.
The concept that drugs are
designed for a specific target is by no means a new one.The conjunction of molecular biology and drug
development that brought Herceptin and its companion diagnostic is just the
beginning of a new chapter in this story.Not surprisingly, given the complexity of the regulatory circuits that
are active in normal and cancer cells, it has become necessary to consider not
just the target molecule itself, but also its biological activity.Many pharmaceutical companies have embarked
on major programs to develop drugs that interact with a particular molecule
that might essential to growth of specific tumors.It has become clear that the success of these
drug development programs is likely to require “intelligent targeted
diagnostics” that recognize that presence of the target is not sufficient; it
must be active as well.A major focus for drug development over the
last ten years has drugs that inhibit the activity of epidermal growth factor
receptor (EGFR), a protein related to HER2, which is over-expressed in many
solid tumors.Several drug companies
including Amgen and ImClone have developed, been granted FDA approval, and
begun to distribute anti-EGFR drugs for treatment of a variety of tumors,
including colon, breast, and lung cancer.The activity of EGFR in regulating cellular growth involves complex
regulatory circuits where EGFR on the surface of a cell activates downstream
effectors which influence proliferation of cells.Once such effector molecule is termed K-ras,
and it has recently been recognized that patients whose tumors do not express
active K-ras do not respond to anti-EGFR drugs.Most recently the FDA has begun to consider requiring that data on the
“genomic profile” of the tumors of patients be included in clinical
trials.It may become policy that such
information provided as part of the development and approval processes.It would appear that the FDA is leaning
toward requiring the co-development of drugs with any companion diagnostic or
genomic profiles to be used to identify the presence of the biologically active
target of the drug.
It is certainly the case that the
emergence of molecular approaches to the identification of drug targets may
serve to support the identification of the target populations for specific new
drugs.While this may accrue to the
advantage of drug makers seeking new markets, it is worth noting that there are
barriers to the acceptance of this approach.A major consideration is the cost in time and patient accrual expenses
for subjects that because of their biological profiles are not included in
phase 1 (toxicity), phase 2 (response), and phase 3 (efficacy) data sets as
part of FDA applications.In the case of
drugs where the target is relatively rare, this can devolve into a great deal
of expense to gain approval for a drug which will find a very small market.This argues that appraisals of target
molecule distribution be part of the early evaluation of drugs and targets.Similarly, it may be difficult to establish
with a reasonable degree of certainty, without recourse to significant basic
research, that the assay method(s) used to assess the levels of the drug target
directly measures the amounts of the active/susceptible form of the target
molecule.
In summary, it is clear that targeted
treatment is likely to become the norm going forward.In terms of medical practice this can be
expected to lead to better patient management, as well as more cost-effective treatment.Pharmaceutical companies can look forward to
using the information gained through the use of molecular diagnostics through a
more rapid, and perhaps mandated, path to drug approval requiring detailed
information as to the particular biological features of tumors, and other
pathological, tissues.Ultimately, what
are now termed companion diagnostics may be the tip of the molecular iceberg
for the coordination of translational research, assay development and drug
design, clinical testing, regulatory approval, and patient management and
treatment.
Warren
Maltzman is currently the Principal of Barsett Consulting (www.barsett.com), which provides guidance in
molecular oncology and pathology. Heearned BA in Biology from the University
of California at Santa Barbara, and his
doctorate in Molecular Biology from the University of California
at Berkeley.Following post-doctoral work in tumor biology
at PrincetonUniversity, he was on the faculty of RutgersUniversity where his research focused
upon the role of the p53 protein in normal cellular growth and cancer.The remainder of his career has been spent in
as a director of research and scientific officer, in the areas of molecular
diagnostics and pathology.He has served
in this capacity in large companies in this space including Quest Diagnostics,
Enzo Biochem, and Ventana Medical Systems, as well several start-ups including
Molecular Staging, Molecular Diagnostics, and most recently Diamics, Inc.He can be reached at wmaltzman@barsett.com.
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