Examining recent approaches to treating solid tumors
January 2012
by Punit Dhillon, OncoSec Medical  |  Email the author
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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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