Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, 414 East Clark Street, Vermillion, SD 57069, USA
*Corresponding author:
Carlos M. Telleria
Division of Basic Biomedical
Sciences
Sanford School of Medicine of The University of South Dakota
414 East
Clark Street, Vermillion, SD 57069, USA E-mail: Carlos.Telleria@usd.edu
Received July 19, 2012; Accepted July 21, 2012; Published July 21, 2012
Citation: Telleria CM (2012) Drug Repurposing for Cancer Therapy. J Cancer Sci
Ther 4: ix-xi. doi:10.4172/1948-5956.1000e108
Drug repurposing; Drug repositioning; Cancer therapy
Background
In the mid-1980s, a French company geared its efforts toward
developing a synthetic steroid capable of blocking the glucocorticoid
receptor in order to potentially treat Cushing’s syndrome. Preclinical
studies revealed that the compound developed, termed RU-38486,
was indeed a potent antiglucocorticoid agent [1], yet with a caveat:
if given to pregnant animals, it terminated pregnancy [2-4]. Thus,
a compound originally developed for treating one disease, rapidly
acquired a different identity, was named mifepristone and investigated
in depth for its abortifacient properties through the blockage of
uterine progesterone receptors [4,5]. In other words, developed with
one intended use, RU-38486 was repurposed for another modality
of use even before gaining approval for medical usage. In the US, the
Food and Drug Administration (FDA) approved mifepristone for
chemical termination of early pregnancy in September 2000 [6]. It took
12 more years for the FDA to support mifepristone for its intended
original use, the treatment of Cushing’s disease. In February 2012, the
FDA approved mifepristone to control hyperglycemia in adults with
endogenous Cushing’s syndrome and not eligible for surgery [7].
The case of mifepristone is an evolving example of many in
drug repurposing, rescue, or repositioning efforts, which entail the
development of a new modality of use for an existing therapeutic
compound—i.e., given a new use to an old molecule. There are many
compounds that have been developed by pharmaceutical companies
and academic institutions throughout the years, in addition to many
natural compounds, that remain without a concrete clinical application;
they are abandoned or underinvestigated compounds [8-10].
Many preclinical developments promise further repurposing for
RU-38486, including other reproductive-related applications such as
oral contraception, menstrual regulation, and emergency contraception
and the amelioration of psychiatric and endocrine disorders
[11,12]. Furthermore, the compound is emerging as a treatment for
endometriosis and uterine fibroids [13]. More recently, we and others
have provided ample evidence for the potential effectiveness of RU-
38486 in oncology by blocking the growth of several cancer cell types
[14-18,19].
The case of RU-38486 is just one example depicting the potentiality
of relatively rapid translation to the clinic applicable to many
abandoned compounds or compounds developed for other purposes.
For instance, metformin, a drug developed and approved to treat type
II diabetes, is currently being intensively investigated to treat breast
cancer [20,21]. Another, perhaps enigmatic case, is that of thalidomide,
currently approved for the treatment of multiple myeloma [22-25].
Thalidomide was originally developed for the treatment of morning
sickness in pregnant women; yet, it had devastating teratogenic side
effects manifested with severe birth defects [26,27].
Discoveries in cancer biology facilitated the development of the
first targeted therapy, imatinib mesylate (a.k.a. Gleevec), which blocks a constitutive active kinase uniquely expressed in chronic myeloid
leukemia (CML) harboring the Philadelphia chromosome translocation
[28]. Yet, the success of Gleevec has been limited by the fact that the
disease evolves in response to the drug, developing new mutations in
the Bcr-Abl protein kinase, making the continuous development of
new drug derivatives a necessity [29,30]. However, the development of
new drugs is extremely costly and there is certainly a gap between the
resources invested in drug development and their translatability into
longer survival for cancer patients. Repurposing existing drugs has to
its advantage the fact that many toxicological studies have been already
done, which reduces the time and cost of approving the compounds for
clinical use. For example, the repurposing of RU-38486 was accelerated
by the fact that all previous toxicological studies had been done before
its approval for early termination of pregnancy. Thus, before being
approved for Cushing’s syndrome, the safety and efficacy of the drug
was evaluated in a clinical trial of only 50 patients; this is because the
compound had the backup of extensive literature on side effects when
used for short term as a contraceptive agent, or for long term in clinical
trials in patients with inoperable meningiomas that have taken the drug
for several years and had mild toxicity considering the clinical benefits
[31].
In order to cooperate in utilizing the existing resources to its
maximum, the National Institutes of Health (NIH) recently created
the National Center for Advancing Translational Sciences (NCATS)
[10,32]. In terms of drug repurposing, the new Institute developed a
funding mechanism to investigate potential new clinical applications,
including cancer therapy, for a group of abandoned drugs in agreement
with the companies holding the propriety rights [32]. NCATS just
launched in July 2012 a pilot NIH-Industry program for discovering
new therapeutic uses of existing molecules in which the NIH will
collaborate with several pharmaceutical companies that will make a list
of 58 drugs available to basic researchers [33]. This is good news for
patients with so-named orphan diseases, i.e, those with low prevalence
and for which R&D from traditional pharmaceutical companies is
very limited. Within such orphan diseases, many cancer types can
be included. There are additional signs of government-controlled
institutions becoming more creative in the process of drug approval. For
instance, going back to mifepristone and its relatively rapid approval to
treat Cushing’s syndrome (also an orphan disease with a prevalence
of ~5,000 patients in the US), the FDA utilized an approach in which the pharmaceutical that develops the medicine, has the total right of
access to the entire of patients being attended by endocrinologists
in the US, and distributes the medicine via a centralized pharmacy.
In this manner, the FDA made appealing to a small company one
of the limitations which forces many pharmaceuticals to put back
compounds in shelves—their reduced marketability. For instance, who
would invest in developing a drug exclusively to target ovarian cancer
when it has a diagnosis rate of ~22,000 patients per year? Nevertheless
70% of those patients will die of the disease within 5 years of diagnosis
due to a lack of alternative treatment approaches. Together, academic
institutions, the government, and the pharmaceutical industries should
work in coordination to become more creative and provide solutions to
members of society that did not choose to develop an orphan disease,
such as many cancers.
Researchers have now access to high throughput screenings to
test old drugs and natural compounds for their potential anti-cancer
properties; however, researchers should also have access to such
chemicals. The NCATS is paving the way towards the access of these
drugs, and the initiative is welcome. Still, as a society, we should
enhance the process of discovery by creating a more dynamic feedback
system between academics, clinicians, patients, patient advocates,
funding institutions, and the private pharmaceutical sector. Bedside
observations in terms of signs and symptoms of patients being treated
for a special condition may underscore off-target effects of a drug.
Some of these observations could lead to the use of certain compounds
for preventing cancer development. For example, it is well documented
by epidemiological studies that women who have used progestin-based
contraceptive pills continuously for at least 5 years, have reduced risk to
develop ovarian cancer for 20 years [34,35]. Clinicians should develop
new hypotheses based on observations and interviews with patients,
and basic researchers should go back to the bench to test compounds
with anticipated anti-growth properties. Let’s not forget that the
most popularly used anticancer agent, platinum, was discovered
serendipitously when microbiologists were investigating the behavior
of bacteria upon changes in voltage and observed growth inhibition
due to electrolysis products from a platinum electrode [36-39]. Cancer
patients deserve that we scientists utilize all tools at our disposal, from
rational drug design for targeted therapy all the way to serendipitous
observations in the laboratory, the clinic, and by the patients themselves.
Hopefully, using all these resources, we will convert cancer into a
treatable chronic disease. The current technological armamentarium
provides cancer researchers with a unique opportunity to find new
targets for old synthetic, abandoned compounds or newly discovered
natural products.
Acknowledgements
This work was supported by National Cancer Institute Grant R15CA164622. I
thank Mr. Nahuel Telleria for the edition of the manuscript.
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