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Examining recent approaches to treating solid tumors
January 2012
SHARING OPTIONS:
One in five people will suffer from skin cancer at
some
point in their lives, and these numbers are steadily increasing. Despite the
advances in sunscreen technology and public awareness of the need
for
protection from the sun, data recently reported in the Dermatology Times demonstrate an increase
in the average U.S.
lifetime risk of one type of skin cancer—invasive melanoma—from 1 in 600 in
1960 to 1 in 50 in 2008. In spite of earlier diagnosis
and advances in
treatment approaches, the age-adjusted number of deaths per 100,000 people per
year is increasing. Moreover, the cost to the healthcare
system and society
continues to escalate. As the populations of the United States and Europe are
aging, the incidence of skin cancer and other solid-
tumor cancers will
increase.
According to the latest United States Cancer Statistics
(2007)
published by the Centers for Disease Control and Prevention, the top
10
cancer types (based on incidence rate) are in the solid tumor category; today,
the priority is likely even higher. Thus, there are clear unmet
medical needs,
and the development of new, cost-efficient and patient-friendly treatments
remain a high priority for both the healthcare community and
patients.
Some challenges of
conventional treatments
Unfortunately, the treatment of solid-tumor cancers, ranging
from melanoma and Merkel
cell carcinoma to cutaneous T-cell lymphoma, continues
to be a major challenge for physicians. For example, despite all of the
advances in drug
discovery and development, it is still difficult to simply
deliver efficient drugs into cancer cells in a safe and effective way.
Meanwhile, current
therapeutic approaches involving surgery, radiation therapy
and chemotherapy each have distinctive and significant drawbacks.
Surgery, the current primary treatment for localized and
operable tumors or lesions, requires resecting the tumor mass and a
surrounding
margin of healthy tissue to ensure that no cancer cells remain at the tumor
site. Surgery can potentially cause both physical disfigurement
and/or
debilitating effects on organ function, and the patient's quality of life has
been shown to be negatively impacted. In addition, surgery can
require a costly
and lengthy hospital stay.
Radiation therapy is sometimes used in conjunction
with
surgery to shrink a tumor before surgical removal, or afterward to destroy any
cancer cells that may remain.
Unfortunately, the combination of surgery and radiation can
be very damaging to critical normal tissues like nerves, blood vessels or vital
organs
such as the heart that are within the designated treatment zone.
Radiation is also an expensive therapeutic approach and requires considerable
expertise, precautionary measures and infrastructure to administer. Radiation brings with it significant
complications, including nausea,
diarrhea, dry mouth, taste alterations, loss
of appetite and the potential for the formation of new cancerous lesions,
including people who get
radiation to the heart; the latter population often
suffers from various types of heart failure after some years.
Chemotherapy is typically a secondary or palliative
treatment to help control systemic or metastatic tumor growth, whereas both
surgery and radiation may be considered local treatments. In response to the
spread of cancer, physicians will administer chemotherapeutic agents that
circulate throughout the body—in a system-wide fashion—and in high
concentrations in order to counter the difficulty that some chemotherapeutic
agents have in reaching and penetrating the cell membrane to bring about the
intended cell death. However, the system-wide administration of
chemotherapeutics often has serious side effects by killing healthy as well as
cancerous cells. This systemic and non-targeted use of anticancer agents
can
produce alopecia, nausea, vomiting, myelosuppression (resulting in reduction in
the number of platelets, red blood cells and immune cells that are
found in the
circulation, and therefore increased susceptibility to infection) and drug
resistance. In addition, chemotherapy is curative for only a
few tumor
types—and all of these traditional treatments are only minimally effective on
aggressive types of cutaneous cancers, especially in later
stages of the
disease.
Some proposed
cutting-edge
approaches
One potential approach to solid tumor treatment involves a
novel class of small-molecule drug candidates called vascular disrupting
agents. Through interaction with vascular endothelial cytoskeletal proteins,
these agents may selectively target and collapse tumor vasculature, thereby
depriving the tumor of oxygen and causing death of the tumor cells.
A second strategy involves the use of novel therapeutic
monoclonal antibody candidates that target CD27, a
member of the tumor necrosis
factor (TNF) receptor superfamily. Anti-CD27 monoclonal antibodies have been
shown to effectively promote anticancer
immunity in mouse models when combined
with T cell receptor stimulation. In addition, CD27 is overexpressed in certain
lymphomas and leukemias and can
be targeted for direct activity by anti-CD27
monoclonal antibodies with effector function against those cancers. There are
numerous other antibody
drugs on the market, some also with linked toxins or
radiation.
Another approach involves the
development of an orally
available nucleoside analogue for various cancers including solid tumors. This
agent could act through a novel DNA single-
strand breaking mechanism, leading
to the production of DNA double strand breaks (DSBs) and/or DNA repair
checkpoint activation; unrepaired DSBs go on
to cause apoptosis or programmed
cell death.
Alternatively, solid tumors might be treated using
a
technique known as tumor ablation, involving the process of physically
destroying the tumor inside the body through various approaches. Radioactive
pellets, less than an inch long and about the width of a pin, can be inserted
into the tumor; subsequently, the pellet releases lethal radioactive
atoms that
irradiate the tumor from the inside out. As the tumor breaks down, it begins to
release antigens that trigger an immune response against the
cancer cells. In
some cases, the body also develops an immune memory against the future return
of tumor cells. A second proposed ablation technique,
called "pulsed electric
current ablation," involves the insertion of electrodes into tumors, which then
emit extremely high-energy electrical
currents. These currents create a
physical reaction that destroys the tumor cells.
Another
separate approach involves the application of local
heating to the tumor utilizing radio frequency techniques. In this instance, a
thermal energy
delivery device can be focused and targeted according to the
shape, size and position of the specific tumor. Adjusting the frequency, phase and amplitude
of the radio waves,
combined with different applicators and adjustment of the patient's position, can
potentially allow a doctor to optimize the
delivery of damaging energy into the
tumor.
Cancer scientists are also interested in attacking solid
tumors by delivering drugs specifically into the diseased tissues. A targeted
approach can result in more efficient therapy while using smaller doses
of
drugs with fewer negative side effects. For example, animal studies with
immune-deficient mice carrying human forms of various cancers have been
simultaneously injected with a variety of anticancer agents and a peptide known
as iRGD. iRGD possesses the ability to find and attach itself to
receptors on
solid-tumor cancer cells and subsequently activate their internal transport
systems so that the peptide is essentially passed through cell
after cell,
moving progressively deeper into the tumor structure. Anticancer drugs
lingering near the peptide molecules may also get pulled into and
through the
tumor mass by this transport mechanism as well, enabling them to attack cancer
cells previously beyond their reach.
By their nature and cellular architecture, solid tumors are
innately equipped to limit the efficacy of most
anticancer drugs. Tumors have poor
vascular systems, which reduce exposure to drugs that have been administered
into the circulation. The lesions are
densely fibrous, which serves as a
physical barrier against transport. In addition, the tumors have high internal
pressures, causing any molecule
attempting to enter the lesion further physical
challenges. The iRGD peptide is engineered to act like a key, switching on the
internal transport
mechanism of the cells so that they actively pull inside
anything that is proximal to certain cell surface receptors. Researchers
believe the iRGD
peptide could penetrate many tumor types and may be useful in
treating most solid tumor cancers. An encouraging aspect of this approach is
that both
the peptide and anticancer drugs are effective together without being
chemically attached to each other.
Yet another promising approach to treating solid tumor
cancers involves targeting the tumor itself without affecting any of the
surrounding
healthy tissue. This ensures the drug or therapeutic agent is
immediately absorbed by the cancer cells and not normal tissues. One such
targeted
therapy could harness a physiologic process known as
"electroporation." Derived from the words "electric" and "pore," this involves
applying a
brief electric field to the cancerous cell. The electrical pulse
causes the temporary formation of pores in the cell's outer membrane—pores that
close
again within seconds once the electric field is discontinued. These
transient pores can improve uptake of certain drugs more than a thousand-fold.
Therapies such as these might offer a compelling set of new
approaches to the treatment of solid
tumor cancers.
Punit Dhillon is
president
and CEO of OncoSec Medical Inc., a biotechnology company
developing
its advanced-stage Oncology Medical System (OMS) ElectroOncology therapies to
treat skin cancer and other solid-tumor cancers.
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