A new personalized cancer treatment – will ‘GliaTrap’ be able to lure and treat cancer cells to prevent tumor recurrence?

What if you get diagnosed with cancer? What if your beloved family member, partner, or friend gets diagnosed with cancer? The news may fill you with fear and despair. Particularly, what if you get diagnosed with glioblastoma (GBM)? GBM is the most aggressive type of brain cancer with an average overall survival of 15~21 months after the first diagnosis. Moreover, GBM patients’ 5-year survival rate is less than 7%, one of the lowest among all cancers. Although treatment for other types of cancer is becoming more and more successful, current treatment options for GBM are largely ineffective and inevitably result in relapse and death. However, at the Laboratory of Cancer Epigenetics and Plasticity at Brown University and Rhode Island Hospital, we are working on innovative new treatments for GBM. One of these projects is called GliaTrap.

What’s Drug discovery process?

How does a new treatment get discovered? The drug discovery process is divided into three steps: 

1. Drug Discovery and Development. 

2. Preclinical Research 

3. Clinical Research. 

A cartoon image of three grey mountains. One mountain is labeled with "Challenge 1: Drug discovery and treatment." One mountain is labeled with "Challenge 2: Pre-clinical research." One mountain is labeled with "Challenge 3: Clinical research." This last mountain is topped with a green flag that says "Goal."
GliaTrap development plan.

During Step 1, researchers elucidate the mechanisms of disease progression, which leads to the discovery and development of a treatment that inhibits the disease process. Once a potential therapeutic candidate is selected, this candidate will go to Step 2 where researchers test the safety, side effects, how the drug affects the body, how the body responds to the drug, and so forth. Preclinical research requires a different laboratory setting than an Academic Research Lab and it should be monitored by a third party (e.g. the FDA in the US). Once this therapeutic candidate is determined to be safe enough, then this treatment will go to Step 3, Clinical Research, where its efficacy in human patients will be tested. This entire process takes about 10-15 years for a single treatment candidate to become available to patients.

Current therapies for GBM include surgical removal, chemotherapy, radiation therapy, or a combination of those. Each treatment modality has its own advantages and disadvantages. Surgery removes most of the bulk tumor but it cannot remove individual cells, which remain in the brain. Chemotherapy is normally administered to treat these remaining GBM cells, however it is challenging to specifically target the distributed GBM cells without killing the surrounding healthy normal cells. Radiation therapy has similar disadvantages as chemotherapy since targeting only cancer cells without damaging the surrounding healthy normal cells is impossible. As explained above, all the current approaches face huge clinical challenges, which makes GBM currently impossible to treat.

 Innovative cancer treatment “GliaTrap” : GliaTrap lures the cancer cells and attacks them.

To address this challenge, we are developing a new technique for GBM therapy: GliaTrap. GliaTrap basically functions just like a Japanese cockroach trap “Gokiburi hoihoi”, a container that houses foods to attract cockroaches and drugs to kill the attracted cockroaches. For the concept of GliaTrap, you should think of cancer cells in the brain like the cockroaches in my example. (Figure 2). GliaTrap uses a biocompatible material called hydrogel, like the container of the Gokiburi hoihoi, to house food and drugs that lure and kill cancer cells. Food for cancer cells is called a chemoattractant, and GliaTrap uses this molecule to lure the residual GBM cells post-surgery to the vicinity of the empty space, just like a cockroach trap uses food to attract cockroaches. Once these cancer cells are attracted to GliaTrap, GliaTrap uses an anti-tumor agent to kill those cells at the vicinity of the empty space without causing significant damage to healthy cells, just like cockroach traps use drugs to kill the cockroaches. We hope that GliaTrap will be able to eliminate the remaining cancer cells from the surgery to prevent tumor recurrence.

GliaTrap can utilize not only anti-tumor agents, but also lure/use the body’s natural immune cells. Anti-tumor agents in GliaTrap can be replaced with immune cell activators, molecules that boost the ability of immune cells to attack cancer cells. GliaTrap can serve as a new treatment delivery method in concert with surgical removal and chemotherapy. GliaTrap combines targeted capture and drug release to increase therapeutic efficacy and safety by selectively killing the cancer cells that surgical removal and chemotherapy might miss. As a result, GliaTrap could increase the survival rate of GBM patients.

On the left is a cartoon cockroach outside of a cartoon trap that has poison disguised as food inside it. The next panel shows the cockroach entering the trap enticed by the food. The last panel shows the cockroach dead inside the trap due to poison.
How cockroaches mimic the GliaTrap system.

Looking forward, GliaTrap can potentially be applied to other types of invasive cancers that don’t have effective current treatments such as pancreatic cancer. Pancreatic cancer has a similar treatment protocol – surgical removal followed by chemotherapy, radiotherapy, or a combination of those. GliaTrap could be implanted into the empty space created by removal of pancreatic cancer cells, and perform in a similar way as described for GBM by choosing an optimal chemoattractant for pancreatic cancer cells. To ensure the coverage of capturing cancer cells, genetic profiles of cancer cells can be investigated and optimal chemoattractants can be utilized. Chemoattractants and therapies can be selected based on the genetic profiles of cancer patients, and GliaTrap can be tailor-made for each patient. With continued effort, GliaTrap could become a platform for combination therapies for various types of cancers contribute to personalized treatments options.

The current challenge for GliaTrap research.


The GliaTrap project has great potential but as every paradigm shifting discovery, it comes with many challenges. It needs a lot more studies to prove its effectiveness and safety before it can be applied to patients.  Ultimately, with our work at the Laboratory of Cancer Epigenetics and Plasticity, we hope to help patients and their loved ones to no longer view the diagnosis of cancer as a death sentence, but rather as a challenge that can be overcome with the right treatment.

References:

1. Louis, D. N. et al. The 2016 World Health Organization Classification of Tumors of the Central  Nervous System: a summary. Acta Neuropathologica 131, 803–820 (2016). 

2. Toms, S. A., Kim, C. Y., Nicholas, G. & Ram, Z. Increased compliance with tumor treating fields  therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of  the EF-14 phase III trial. J Neurooncol 141, 467–473 (2019). 

3. Wang T, Suita Y, Miriyala S, Dean J, Tapinos N, Shen J. Advances in Lipid-Based Nanoparticles for Cancer Chemoimmunotherapy. Pharmaceutics. 2021; 13(4):520. https://doi.org/10.3390/pharmaceutics13040520

4. Tapinos, N., Sarkar, A. & Martinez-Moreno, M. Systems and Methods for Attracting and Trapping  Brain Cancer Cells. (2017).

Indigenizing Colonization: How Indigenous Knowledge Can Help Us Do Better When Looking to Colonize Other Planets

When you think of colonizing a planet, your mind may turn to a science fiction-like existence: new and cutting-edge technologies you could never have dreamed of; humans living in enclosed habitats; and harsh, unforgiving environments that must be tamed in order to survive. What you may not think of is that humans have done it before—here, on Earth.

I am a member of the Shinnecock Nation and a planetary scientist. Originally, I saw my native identity as extraneous to my scientific career. How could my indigenous knowledge ever help me when researching a completely different world? But the more I delved into my work, the more I saw there were problems that could be solved using “Two Eyed Seeing”

Two Eyed Seeing is a term originally coined by Mik’maw elder Albert Marshall and introduced to me by Dr. Roger Dube, a Mohawk Native from the Rochester Institute of Technology. The term refers to using western and indigenous scientific approaches simultaneously. The indigenous approach to science places an emphasis on observation and working in a way that is synergistic with what the natural world already offers, while western science follows the typical scientific method of posing a question and conducting an experiment. Importantly, because of the focus on synergy with the natural world, indigenous science generally has a lower impact on environmental surroundings when used responsibly.

Multi-colored red and yellow corn on a black tabletop
The multi-colored kernels of the Bear Island flint corn planted during the experiment.

The inaugural manned mission to Mars is expected in 2024 for SpaceX and in the 2030’s for NASA, and with humans reaching the Red Planet we may be headed towards colonization. The first step to approaching Mars’ colonization through a more indigenous lens is to remember that we must view the planet as a living thing and as a provider. In many North American indigenous cultures, we refer to the land that indigenous people inhabit as “Turtle Island”, a term that harkens back to a creation story1 which describes how we live on the back of a giant turtle moving through the oceans. In that sense, while you have been permitted to live on this being, you must also respect it, for it too is alive. Mars may not be as prolific a provider as Earth, but there are resources there that can be worked in tandem with rather than simply exploited. We don’t have to be a resource-hungry culture going from planet to planet using up everything that we can and moving on.

Every kilogram of resources imported from Earth costs large amounts of money, fuel, and time to reach Mars. If we brought fertilizer and soil there, both highly dense items, these would be literally worth more than their weight in gold. Thus, the respect for the resources on Mars becomes important not only from a moral standpoint, but also from economic and logistical standpoints. On Mars, water-ice is abundant beneath the surface, especially in polar regions. It can be melted for drinking, daily necessities and other purposes. It can also be transformed into rocket fuel by splitting the water molecules into its constituent hydrogen and oxygen atoms. Building materials found on Mars, such as easily accessible iron from meteorites on the surface and regolith,  could be used to build habitats with 3D printing. Through an indigenous approach we can learn to utilize these resources while sustaining them for long-term growth and future exploration. Traditionally, many indigenous communities in the Americas grew their own food, amended soil naturally and organically, and were able to create a self-sufficient, near-vegetarian community. Corns, beans, and squash, known to many tribes as “the three sisters”, were grown together in a beneficial, symbiotic arrangement quite different from the monocrop, non-rotational farming that is currently popular in the food growth industry. The beans added nitrogen back to the soil to be used by the corn and squash, the corn provided a pole for the beans to climb, and the squash served as a living mulch that fought off pests with its prickly texture. These three foods together rounded out the complete nutritional needs of a human, however they were not the varieties you are used to buying in a grocery store.

Twenty-four small green pots with white labels sticking out of their tops, all are placed in black crates
Each pot had two seeds planted in it. The pots in the foreground have Miraclegro soil, the next set has MGS-1, and the last set has MGS-1C (the global mars soil simulant with clay added).

Due to colonization and the forced removal of native peoples, as well as the assimilation tactics used, most tribes no longer grow their own food and many heritage species have been lost. The switch to grocery store varieties has seriously impacted native communities, especially those in “food deserts” where the reservation residents do not have a true supermarket nearby. The increased sugars in today’s varieties, along with low food budgets forcing people to choose less healthy options has caused an epidemic of Type 2 diabetes, with rates as high as 60% among the adults of some tribes. Traditional or “heritage” indigenous foods are higher in nutritional value and many were cultivated to be resistant to various specific environmental conditions. These resistances were developed over thousands of years of seed selection for desirable traits and this work can be utilized and continued in an off-planet habitat where a unique and unfamiliar environment will allow certain seeds to thrive and become the newly selected seeds.

According to a talk given at the American Indian Science and Engineering Society Conference in 2020 by Dr. Gioia Massa of NASA’s Kennedy Space Center, the current focus for food growth in a Mars habitat is on crops that can be eaten fresh or, with the future addition of a heating apparatus, staple crops that can be consumed with minimal preparation and cooking. While using the three sisters as the main crops may not be viable for the early missions, as the post-preparation needs of a crop are fundamentally important to optimizing astronaut time, the variety of each of the crops considered, as well as the production methods, can be scrutinized as well.

One method that would save significant transportation cost and would put us a step closer to future terraforming would be to use a direct sow method of plant production; in other words, to use the soil available on Mars to grow the plants. The general martian soil is not hospitable to plants; it is sandy, low in nutrients, and in some areas has high levels of salts and perchlorates which are poisonous to the emerging plant life. However, that doesn’t mean that there aren’t areas which may be hospitable.

My main research focus is on the geochemistry of alteration minerals on Mars, specifically on clays. Clays were critical for the development of early life on Earth. Clay particles provide a high surface area and protective layers for microbes as well as a high level of preservation potential. For this reason, they may be the best chance of finding possible traces of former life. Clays may also be the key to the proliferation of life on the planet.

Eight small green pots with white labels sticking out of their tops. Two of the pots have small green sprouts
This photo was taken just as the last seedlings emerged from the clay amended mars soil (MGS-1C). The two in pot 4 and the one in pot 5 emerged earlier on, but the single seedlings in pot 1 and 2 can just be seen poking out of the soil by this time. All germinated seedlings survived healthily to the end of the experiment.

With the support of my PhD advisors Jack Mustard and Jim Head, I decided to test the viability of growing heritage crops in martian soils, and to determine if the soils with a large clay component would allow for viable plants to grow. The plant variety I chose was Bear Island flint corn, which was traditionally grown on islands with isolated ecosystems by the Chippewa/Ojibwa tribe and was ground into meal and flour. This variety was recently popularized within indigenous communities in the Midwest by the tribal food sovereignty activist Winona LaDuke because it is resistant to drought, high winds, and contains nearly 12% protein, more than twice the amount as other varieties.

I planted the corn in three soil types: MiracleGro Seed Starter Formula (a control for comparison), Exolith lab’s MGS-1 (a martian soil simulant representative of the general martian soil composition), and MGS-1C (an amended version of MGS-1 that contains 40% smectite clays and is representative of the soil at the Mars Perseverance planned landing site). The corn was kept in a grow chamber at ideal conditions for corn growth (65% humidity, 16 hours of light, and 22ºC), cared for daily by the wonderful folks at the Brown Plant Environmental Center, and never fed fertilizer or other additives. Other studies that have successfully grown plants in martian soils have mainly added nitrogen based fertilizer, which would be extremely expensive to bring due to its weight.

The seeds planted in the MiracleGro had an 81.25% germination rate (13/16); they germinated in only 4 days after planting. The seeds in the MGS-1 soil had a 0% germination rate (0/16); nothing was able to grow at all. Interestingly, the seeds in the MGS-1C had a 31.25% germination rate (5/16) and ranged in time to germination between 17-21 days. The published germination time for this variety of corn was 9-14 days under normal conditions, and admittedly these conditions were far better than normal. The published germination time is significantly more than that shown with the MiracleGro soil, but less than that seen from the MGS-1C seeds.

Three clear plastic cases in a grow chamber each with eight green pots inside
The potted seeds were placed in a grow chamber in the Brown Plant Environmental Center which was kept at 65% humidity and 22ºC with 16 hours of light. The trays originally had plastic lids to encourage the seedling germination, but after they began to emerge in each tray, the lid was removed as to not inhibit growth.

In martian-type soil with a clay component, the corn was able to germinate. This means that we can use the soils present on the planet rather than bringing in other resources if a landing site with sufficient clay content is chosen. The benefit of using certain heritage plants is their viability in difficult environmental conditions. Corn may not be a crop grown by the first missions, but looking past the common plant varieties seen today and considering traditional heritage crops will still allow knowledge of indigenous food practices to be utilized. By using a direct sow method, the plants that are grown in these soils will begin to produce seeds more adapted to the planet, continuing the centuries-old practice of selecting plants for hardiness. . 

Other native principles, such as using all parts of a resource, similar to the zero waste movement today, point towards a sustainable cycle where we could use the inedible parts of plants to compost and rejuvenate the soils, or perhaps even use pre-composted human waste to add fertilizer and increase rates of germination and growth. Native people speak about building for the seventh generation. Mars will eventually be colonized, so we should take steps now to ensure that it will be done in a way that we can be proud of seven generations later. I believe that by considering the people who were most affected by the colonization that occurred on this planet, we can learn the lessons we need to effectively and honorably colonize another.