The Treatment of Solid Tumors: Some Recent Approaches

By Punit Dhillon

At some point in their lives, one in five people will suffer from skin cancer, and the fraction is steadily rising.  In spite of innovation in sunscreen technology and public attention to the need to be shielded from the sun, data reported recently by Dermatology Times show a rise in the average American lifetime risk of one skin cancer variety—invasive melanoma—from 1/600 in 1960 to 1/50 in 2008.  Despite previous diagnosis and innovations in approaches to treatment, the age-adjusted number of annual deaths per 100,000 population is rising.  Additionally, the expense to the healthcare system and society continues to increase.  As U.S. and European populations age, the incidence of skin cancer and other solid tumor cancers will grow.  According to the latest United States Cancer Statistics, published by the Centers for Disease Control and Prevention in 2007, the top 10 cancer types (based on incidence rate) are in the solid tumor category; today the priority is probably even higher.  Thus, there are clear medical needs going unmet and the creation of novel, cost-efficient and patient-friendly treatments remain a top priority for both the healthcare community and patients.

Various challenges of traditional treatments

The treatment of solid tumor cancers, which range from melanoma and Merkel cell carcinoma to cutaneous T-cell lymphoma, continues to be a substantial challenge for physicians.  For example, in spite of innovations in drug discovery and development, it is still challenging to simply deliver efficient drugs into cancer cells in a safe and effective manner.  Meanwhile, today’s therapeutic approaches—involving surgery, radiation therapy and chemotherapy—each have characteristic and major drawbacks.

Surgery, the current first-line treatment for localized and operable tumors or lesions, requires resecting the tumor mass and a surrounding boundary of healthy tissue to make sure that no cancer cells remain at the tumor site.  Surgery can potentially cause physical disfigurement and/or debilitating effects on organ function, and the patient quality of life has been demonstrated to be negatively impacted.  Also, surgery can require an expensive and long hospital stay.

Radiation therapy is occasionally used in conjunction with surgery to shrink a tumor prior to surgical removal, or afterward to destroy any cancer cells that might remain.  Yet surgery plus radiation can damage important normal tissues like nerves, blood vessels, or vital organs such as the heart that are within the designated zone of treatment.  Radiation is also a costly therapeutic approach, and demands substantial expertise, precautionary measures and infrastructure to administer.  Radiation entails major complications, such as nausea, diarrhea, dry mouth, taste alterations, loss of appetite, and the potential for the formation of new cancerous lesions. Those who get radiation to the heart often suffer from various types of heart failure in subsequent years.

Typically, chemotherapy is a secondary or palliative treatment to help mitigate systemic or metastatic tumor growth, whereas surgery and radiation may be considered local treatments.  In response to cancer’s spread, physicians will administer chemotherapeutic agents that circulate throughout the body, systemically and in high concentrations, to counter the challenge that some chemotherapeutic agents have in reaching and penetrating the cell membrane to trigger cell death.  Yet the system-wide use of chemotherapeutics frequently has major side effects by killing healthy as well as cancerous cells.  This systemic and non-targeted administration of anticancer agents can trigger alopecia; nausea; vomiting; myelosuppression; and drug resistance.  Chemotherapy is curative for only a few tumor types.

Additionally, all of these conventional treatments are only minimally effective on aggressive types of cutaneous cancers, especially in later stages of the disease.

Some potential approaches

We now offer an abbreviated look at some current approaches to override these challenges in treating solid tumors.

One possible strategy for solid tumor treatment involves a new class of small-molecule drug candidates called vascular disrupting agents.  Via 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.

Another approach involves the use of new therapeutic monoclonal antibody candidates that target CD27, a member of the tumor necrosis factor (TNF) receptor superfamily.  Anti-CD27 monoclonal antibodies have been demonstrated to effectively promote anticancer immunity in mouse models when combined with T cell receptor stimulation.  In addition, CD27 is overexpressed in various lymphomas and leukemias and can be targeted for direct activity by anti-CD27 monoclonal antibodies with effector function against those cancers.  There are many other antibody drugs on the market, some also with linked toxins or radiation.

A third tactic involves the creation 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 could be treated using a technique called tumor ablation, which involves destroying the tumor inside the body via various approaches.  Radioactive pellets, shorter than an inch and approximately the width of a pin, can be inserted into the tumor; the pellet subsequently emits lethal radioactive atoms that irradiate the tumor from the inside out.  As the tumor breaks down, it starts to release antigens that trigger an immune response against the cancer cells.  Sometimes, the body also develops an immune memory against the future return of tumor cells.  Another proposed ablation technique, called “pulsed electric current ablation,” involves the insertion of electrodes into tumors, which subsequently emit very high-energy electrical currents; these currents create a physical reaction that destroys the tumor cells.

A separate approach involves applying local heating to the tumor using radio frequency techniques.  In this instance, a thermal energy delivery device can be focused and targeted according to the shape, size and position of a specific tumor.  Adjusting the frequency, phase, and amplitude of the radio waves, combined with different applicators and adjustment of the patient’s position, could conceivably permit 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 diseased tissues. Such a targeted approach can result in more efficient therapy while using smaller drug doses with fewer negative side effects.  For example, in animal studies, immune-deficient mice carrying human forms of various cancers have been simultaneously injected with a range of anticancer agents and a peptide known as iRGD.  iRGD can find and attach itself to receptors on solid tumor cancer cells and later 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, enabling them to attack cancer cells previously beyond their reach.

By their nature and cellular architecture, solid tumors are equipped to limit the efficacy of most anticancer drugs.  Tumors have poor vascular systems, which reduces exposure to drugs that have been administered into the circulation.  The lesions are densely fibrous, which serves as a physical barrier against transport.  Also, the tumors have high internal pressures, causing further physical challenges to any molecule attempting to enter the lesion.  The iRGD peptide is designed to act like a key, switching on the internal transport mechanism of the cells so that they absorb anything that is proximal to certain cell surface receptors.  Researchers believe the iRGD peptide could penetrate many tumor types and might 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.

Yet another promising strategy for treating solid tumor cancers involves targeting the tumor itself without affecting any of the surrounding healthy tissue.  This ensures that the drug or therapeutic agent is absorbed at once 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 triggers the temporary creation 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 various drugs more than a thousand-fold.

Several electroporation systems have been manufactured that consist of a generator that creates the pulsed electric field, and various handheld applicators with electrode needles at their proximal ends.  The applicator delivers a controlled electric pulse to the cancer cells, thus causing any cancer cells within the affected region to undergo electroporation.  The cell takes up therapeutic agents within the region of electroporation.

This technology platform is being developed for use in two varieties of anticancer therapies:  electrochemotherapy and electroimmunotherapy.  In the former, an anticancer drug is injected into a targeted tumor; the lesion is then electroporated and the drug carries out its planned mechanism of action in killing the cell.  As a result of the targeted, local therapy, the amount of drug needed to kill the cells is substantially less than that required in traditional, non-targeted chemotherapy.  The lower quantity of systemic drug (cytotoxic agent) reduces harmful side effects linked to traditional chemotherapy. Electroimmunotherapy, the second application of electroporation, involves the use of a gene encoding a specific cytokine, a substance known to boost the human immune system against cancer cells.  An immune response can have both a local and a distant effect against cancerous cells.  These therapeutic approaches have been shown to be safe and effective across various types of tumors.  Both patient outcomes and pharmacoeconomic benefits are substantial.  This technology is in clinical testing in North America and is available for commercial sale in some European countries.

Therapies such as those discussed here may provide a compelling set of novel approaches to the treatment of solid tumor cancers.

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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. He can be reached at pdhillon@oncosec.com.