Two years ago, European media sources published a story about a scientist who was running in the London Marathon to raise funds for some groundbreaking cancer research. That scientist was Dr. Mo Keshtgar, a professor of Cancer Surgery and Surgical Oncology at University College London. Dr. Keshtgar was hoping to launch a clinical trial on photodynamic therapy (PDT), a light-based treatment strategy that holds great promise for the future of cancer medicine.
PDT is a clinically approved, minimally invasive method for the treatment of various cancers. The treatment eliminates tumor cells by combining light with a photosensitizing agent. Light activation of the agent results in an energy transfer process that ultimately leads to the cancer’s elimination.
Three basic factors account for PDT’s therapeutic impact: (1) direct killing of tumor cells; (2) indirect damage to the tumor’s blood vessel supply; and (3) activation of the anti-cancer immune defenses. If successfully funded, Keshtgar’s clinical trial will focus on women with newly diagnosed breast cancer.
The first phase of this trial involves recruiting patients who are willing to undergo the treatment. A total of 30 women will be monitored over the course of three months and compared to a matched group of patients treated initially with surgery. The purpose is simply to ascertain whether PDT can achieve the same outcome provided by surgery—that is, complete removal of the tumor.
Unfortunately, because PDT is still considered “unproven” as a breast cancer treatment, all of the PDT-treated patients will need to consent to later undergoing mastectomy, chemotherapy and radiotherapy. This combination of treatments is the current “standard of care” in modern oncology, and medical experts assert that it is too risky to submit patients to PDT alone because there is not enough evidence that it can protect patients from a relapse or from progression of the disease.
Over the past few decades, PDT has evolved considerably, and now represents a very potent technology that Keshtgar and his colleagues believe could eventually supplant surgery, at least in some cases. In particular, the treatment could be considered for breast cancer patients who are either unfit for surgery (due to advanced age or poor physical condition) or who refuse getting a mastectomy for personal reasons.
One reason PDT was largely ignored as a breast cancer treatment option until recently was that that the first-generation photosensitizers—those agents that capture light’s energy and then harness that energy to kill cancer cells—were not selective enough for the cancer. This resulted in excessive skin sensitivity to light (also called photosensitivity) for days or even weeks after the treatment. The new agents, however, are far more selective for cancer cells and result in little or no photosensitivity afterward.
In addition, the use of lasers enables the light-based treatment of cancers deep inside the body. The combination of PDT with ultrasound has the potential for an even stronger treatment effect—all without the adverse side effects of surgery, chemotherapy and radiotherapy. (Note: We addressed the PDT-ultrasound approach to breast cancer in a previous Discoveries article.)
Let’s consider some of the recent evidence for using PDT for the treatment of breast tumors. In particular, we will take a look at recent progress in assessing different photosensitizers for PDT, as well as various combination strategies that could improve the therapeutic index of this innovative approach to treating breast cancer.
Modifying the Tumor’s Microenvironment
The tumor microenvironment refers to the internal conditions and populations of cells within the tumor. Some of these are tumor cells, while others are non-tumor cells that interact with the tumor cells. Various factors can be produced by the tumor microenvironment non-tumor cells that affect the tumor cells and cause them to proliferate or behave differently.
We now know that cells exposed to low blood sugar (glucose) are less sensitive to PDT using the photosensitizer, aminolaevulinic acid (ALA). In human breast cancer cells deprived of glucose, ALA-PDT’s effectiveness was shown to be significantly reduced. (As an aside, low blood sugar is also referred to as hypoglycemia, a condition that often occurs when a diabetic person takes too much insulin.)
In addition, tumors tend to thrive in a more acidic environment when compared to their surrounding normal tissues. This low pH conditions appear to enhance the tumor’s uptake of several photosensitizers. Moreover, by injecting glucose into the tumor, it is possible to further increase the acidity—thus making the tumor cells even more sensitive to PDT treatment. “If the low tumor pH explains the selective localization of such drugs, the clinical outcome of PDT can be improved by combining it with glucose injections,” the Río Cuarto researchers state.
Blending Nanomedicine with Photodynamics
In the field of nanotechnology, scientists are developing photosensitizer “delivery vehicles” in the form of what are called liposomes. These liposomes serve to transport the photosensitizer more effectively into the cancer cell, and their activity can be enhanced by light, temperature or pH changes. Some liposomes are said to be “phototriggered”—or triggered by light—to release their contents inside the cancer cells. In this novel approach, the liposome reaches the cancer cells and is readily transported across the cell membrane. Exposing the cancer cells to light triggers the release of the photosensitizer from inside the liposome, resulting in destruction of the cancer cell or in the cell’s increased fluorescence, which can be used for diagnostic purpose (photodiagnosis).
Examples of the phototriggering of liposomes were described in a report published in the 19 December 2014 International Journal of Nanomedicine. Cancer cells are heavily dependent on a form of metabolism known as aerobic glycolysis. Agents that inhibit this metabolic process have been shown to enhance the effectiveness of PDT.
A recent study showed that two of these agents, 2-DG and 3-bromopyruvate, boosted PDT’s ability to selectively destroy human breast cancer cells. Because the drugs target this unique aspect of cancer cell metabolism, they may be more selective for cancer cells and may work well in tandem with PDT, as reported in the 12 December 2014 issue of Photochemical & Photobiological Sciences.
Despite major advances in its treatment and management, breast cancer continues to pose an enormous challenge to modern medicine. In the coming years, we can expect the pharmaceutical industry and research institutes to launch numerous clinical trials to assess PDT in conjunction wit—or in some cases as a replacement for—more conventional methods of treating breast cancer and other solid tumors.
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Sine J, Urban C, Thayer D, Charron H, Valim N, Tata DB, Schiff R, Blumenthal R, Joshi A, Puri A. Photo activation of HPPH encapsulated in “Pocket” liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts. Int J Nanomedicine. 2014 Dec 19;10:125-45
Feng X1, Zhang Y, Wang P, Liu Q, Wang X. Energy metabolism targeted drugs synergize with photodynamic therapy to potentiate breast cancer cell death. Photochem Photobiol Sci. 2014 Dec 12;13(12):1793-803.
Xu C, Wang Q, Feng X, Bo Y. Effect of evodiagenine mediates photocytotoxicity on human breast cancer cells MDA-MB-231 through inhibition of PI3K/AKT/mTOR and activation of p38 pathways. Fitoterapia. 2014 Oct 16;99C:292-299. Epub ahead of print
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