Despite the continued advancement of immunotherapy in the fight against cancer, chemotherapy remains the gold standard of cancer treatment. For decades, oncologists have used chemotherapy to trigger apoptosis, a kind of programmed cell death that occurs naturally in the cells of healthy tissue, in cancer cells. But some of the deadliest cancers, including pancreatic and lung cancer, have been stubbornly resistant to chemotherapy1. Apoptosis has been inadequate in attacking the cells that make up these cancers.
There is, however, hope. In recent years, dozens of researchers across the world have developed several alternative approaches to destroying cancer cells. These approaches involve a combination of natural and synthetic compounds that have shown promise in theory or in preclinical research. Some may now be nearing Phase I clinical trials. Here’s a look at three of them, as described in a recent interview with a researcher from Texas State University.
Starve the cancer cells
One alternative to apoptosis involves depriving cancer cells of nutrients through a process called autophagy. Through this method, cancer patients receive drugs that deprive cancer cells of the ability to detect nutrients around them. The cells eventually begin to starve and, out of desperation, essentially eat themselves. Autophagy, then, kills cancer cells by tricking them into self-destructing1.
There are not many drugs on the market that treat cancer by triggering autophagy, but scientists are currently looking into more prospects. These prospects include some natural substances, such as plants and fungi, that could function as autophagy-inducing compounds. Such compounds, however, may pose challenges in Phase I clinical trials: it can be difficult to control the extent to which autophagy takes place – there may be a high risk of the process spreading beyond cancer cells to healthy cells – making it difficult to determine the ideal dosage of an autophagy-inducing compound, one of the central functions of Phase I2. Any compound designed to trigger autophagy will likely need to be developed in conjunction with a compound designed to limit the process to cancer cells.
Blow the cells up
Another alternative approach to the destruction of cancer cells is paraptosis, a process through which a cancer cell is filled with tiny cavities called vacuoles. Eventually, the cell surpasses its critical mass of vacuoles, causing it break apart and die. One compound derived from a fungus, ophiobolin A, has demonstrated the ability to destroy cancer cells that survived chemotherapy in mice. Researchers ultimately hope to introduce the compound to humans in Phase I trials. Before they can, though, they will need to contend with a number of obstacles, not least of which is the difficulty of getting ophiobolin A – as well as many drugs for numerous diseases, for that matter – past the barrier that separates the bloodstream from the brain. For this reason, researchers at Oxford are currently working on the development of so-called “nanovehicles” that can help usher such compounds past this barrier1. If they are successful, a paraptosis-inducing alternative to chemotherapy may find its way into first-in-human clinical trials.
Lock the cells in place
When the active destruction of cancer cells fails, a more passive approach is available. Cancer cells have malleable skeletons composed of microtubules that enable them to wriggle through tissue and into the bloodstream, allowing them to travel to other parts of the body. Researchers are now working on a compound derived from daffodils that they believe could freeze those skeletons in place. This treatment would have a two-pronged approach. First, by making the skeletons rigid, it would deprive them of the malleability necessary to fit through the passageways into the bloodstream, preventing metastasis. Secondly, with stiff skeletons, the cells are unable to divide and multiply; when they reach the end of their lifespan, they die without leaving any new cells in their place. Of these three alternatives to chemotherapy, this last approach is closest to Phase I1. However, like the first two, there are obstacles to its delivery that will need to be overcome if it is to be effective.
With pancreatic cancer, lung cancer, and others, traditional treatment through apoptosis has proven insufficient. But when medical progress encounters an obstacle, it has consistently shown a capacity to find outside-the-box ways around it. These three alternative approaches to the destruction of cancer cells are manifestations of this capacity. If and when they enter clinical trials, we may find that some of the most elusive cancers are no longer so elusive.
1 Bengsch, Danielle; Finding cures for incurable cancers in nature; ResearchGate; 3 June 2016
2 Levine, Beth; Packer, Milton; Codogno, Patrice; Development of Autophagy Inducers in Clinical Medicine; American Society for Clinical Investigation; 2 January 2015