One in five people will suffer from skin cancer at somepoint in their lives, and these numbers are steadily increasing. Despite theadvances in sunscreen technology and public awareness of the need forprotection 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 in1960 to 1 in 50 in 2008. In spite of earlier diagnosis and advances intreatment approaches, the age-adjusted number of deaths per 100,000 people peryear is increasing. Moreover, the cost to the healthcare system and societycontinues to escalate. As the populations of the United States and Europe areaging, the incidence of skin cancer and other solid-tumor cancers willincrease.
According to the latest United States Cancer Statistics(2007) published by the Centers for Disease Control and Prevention, the top 10cancer 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 treatmentsremain a high priority for both the healthcare community and patients.
Some challenges ofconventional treatments
Unfortunately, the treatment of solid-tumor cancers, rangingfrom melanoma and Merkel cell carcinoma to cutaneous T-cell lymphoma, continuesto be a major challenge for physicians. For example, despite all of theadvances in drug discovery and development, it is still difficult to simplydeliver efficient drugs into cancer cells in a safe and effective way.Meanwhile, current therapeutic approaches involving surgery, radiation therapyand chemotherapy each have distinctive and significant drawbacks.
Surgery, the current primary treatment for localized andoperable tumors or lesions, requires resecting the tumor mass and a surroundingmargin of healthy tissue to ensure that no cancer cells remain at the tumorsite. Surgery can potentially cause both physical disfigurement and/ordebilitating effects on organ function, and the patient's quality of life hasbeen shown to be negatively impacted. In addition, surgery can require a costlyand lengthy hospital stay.
Radiation therapy is sometimes used in conjunction withsurgery to shrink a tumor before surgical removal, or afterward to destroy anycancer cells that may remain.
Unfortunately, the combination of surgery and radiation canbe very damaging to critical normal tissues like nerves, blood vessels or vitalorgans such as the heart that are within the designated treatment zone.Radiation is also an expensive therapeutic approach and requires considerableexpertise, precautionary measures and infrastructure to administer. Radiation brings with it significantcomplications, including nausea, diarrhea, dry mouth, taste alterations, lossof appetite and the potential for the formation of new cancerous lesions,including people who get radiation to the heart; the latter population oftensuffers from various types of heart failure after some years.
Chemotherapy is typically a secondary or palliativetreatment to help control systemic or metastatic tumor growth, whereas bothsurgery and radiation may be considered local treatments. In response to thespread of cancer, physicians will administer chemotherapeutic agents thatcirculate throughout the body—in a system-wide fashion—and in highconcentrations in order to counter the difficulty that some chemotherapeuticagents have in reaching and penetrating the cell membrane to bring about theintended cell death. However, the system-wide administration ofchemotherapeutics often has serious side effects by killing healthy as well ascancerous cells. This systemic and non-targeted use of anticancer agents canproduce alopecia, nausea, vomiting, myelosuppression (resulting in reduction inthe number of platelets, red blood cells and immune cells that are found in thecirculation, and therefore increased susceptibility to infection) and drugresistance. In addition, chemotherapy is curative for only a few tumortypes—and all of these traditional treatments are only minimally effective onaggressive types of cutaneous cancers, especially in later stages of thedisease.
Some proposedcutting-edge approaches
One potential approach to solid tumor treatment involves anovel class of small-molecule drug candidates called vascular disruptingagents. Through interaction with vascular endothelial cytoskeletal proteins,these agents may selectively target and collapse tumor vasculature, therebydepriving the tumor of oxygen and causing death of the tumor cells.
A second strategy involves the use of novel therapeuticmonoclonal antibody candidates that target CD27, a member of the tumor necrosisfactor (TNF) receptor superfamily. Anti-CD27 monoclonal antibodies have beenshown to effectively promote anticancer immunity in mouse models when combinedwith T cell receptor stimulation. In addition, CD27 is overexpressed in certainlymphomas and leukemias and can be targeted for direct activity by anti-CD27monoclonal antibodies with effector function against those cancers. There arenumerous other antibody drugs on the market, some also with linked toxins orradiation.
Another approach involves the development of an orallyavailable nucleoside analogue for various cancers including solid tumors. Thisagent could act through a novel DNA single-strand breaking mechanism, leadingto the production of DNA double strand breaks (DSBs) and/or DNA repaircheckpoint activation; unrepaired DSBs go on to cause apoptosis or programmedcell death.
Alternatively, solid tumors might be treated using atechnique known as tumor ablation, involving the process of physicallydestroying the tumor inside the body through various approaches. Radioactivepellets, less than an inch long and about the width of a pin, can be insertedinto the tumor; subsequently, the pellet releases lethal radioactive atoms thatirradiate the tumor from the inside out. As the tumor breaks down, it begins torelease antigens that trigger an immune response against the cancer cells. Insome cases, the body also develops an immune memory against the future returnof tumor cells. A second proposed ablation technique, called "pulsed electriccurrent ablation," involves the insertion of electrodes into tumors, which thenemit extremely high-energy electrical currents. These currents create aphysical reaction that destroys the tumor cells.
Another separate approach involves the application of localheating to the tumor utilizing radio frequency techniques. In this instance, athermal energy delivery device can be focused and targeted according to theshape, 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, canpotentially allow a doctor to optimize the delivery of damaging energy into thetumor.
Cancer scientists are also interested in attacking solidtumors by delivering drugs specifically into the diseased tissues. A targetedapproach can result in more efficient therapy while using smaller doses ofdrugs with fewer negative side effects. For example, animal studies withimmune-deficient mice carrying human forms of various cancers have beensimultaneously injected with a variety of anticancer agents and a peptide knownas iRGD. iRGD possesses the ability to find and attach itself to receptors onsolid-tumor cancer cells and subsequently activate their internal transportsystems so that the peptide is essentially passed through cell after cell,moving progressively deeper into the tumor structure. Anticancer drugslingering near the peptide molecules may also get pulled into and through thetumor mass by this transport mechanism as well, enabling them to attack cancercells previously beyond their reach.
By their nature and cellular architecture, solid tumors areinnately equipped to limit the efficacy of most anticancer drugs. Tumors have poorvascular systems, which reduce exposure to drugs that have been administeredinto the circulation. The lesions are densely fibrous, which serves as aphysical barrier against transport. In addition, the tumors have high internalpressures, causing any molecule attempting to enter the lesion further physicalchallenges. The iRGD peptide is engineered to act like a key, switching on theinternal transport mechanism of the cells so that they actively pull insideanything that is proximal to certain cell surface receptors. Researchersbelieve the iRGD peptide could penetrate many tumor types and may be useful intreating most solid tumor cancers. An encouraging aspect of this approach isthat both the peptide and anticancer drugs are effective together without beingchemically attached to each other.
Yet another promising approach to treating solid tumorcancers involves targeting the tumor itself without affecting any of thesurrounding healthy tissue. This ensures the drug or therapeutic agent isimmediately absorbed by the cancer cells and not normal tissues. One suchtargeted therapy could harness a physiologic process known as"electroporation." Derived from the words "electric" and "pore," this involvesapplying a brief electric field to the cancerous cell. The electrical pulsecauses the temporary formation of pores in the cell's outer membrane—pores thatclose again within seconds once the electric field is discontinued. Thesetransient pores can improve uptake of certain drugs more than a thousand-fold.
Therapies such as these might offer a compelling set of newapproaches to the treatment of solid tumor cancers.
Punit Dhillon ispresident and CEO of OncoSec Medical Inc., a biotechnology company developingits advanced-stage Oncology Medical System (OMS) ElectroOncology therapies totreat skin cancer and other solid-tumor cancers.
