Clinical Researcher—December 2024 (Volume 38, Issue 6)
PEER REVIEWED
Deepika Khedekar, MPharm
This article highlights the urgent need to explore solutions that enhance the robustness and efficiency of cancer clinical trials and research programs. It delves into the role of the microgravity environment in advancing cancer research, focusing on novel experiments that have enabled us to accelerate cancer cell growth in microgravity, shorten drug testing timelines, develop 3D tumor spheroids with much higher resolution in space, and crystallize the KRAS protein with five times the signal-to-noise ratio observed on Earth. These developments hold the potential to expedite clinical research on Earth by providing detailed insights into cancer cell development, driving drug development, and helping clinical trial researchers better understand how drug-target pairs might behave in trials. The article also examines the challenges and risks that clinical research programs may face in the future as they integrate microgravity experiments into their research.
In response to these challenges, the article proposes a holistic framework with a two-fold approach. The first part of the framework aims to summarize the findings from all space-based cancer research experiments conducted so far, and the second part offers a comprehensive blueprint for incorporating this novel microgravity environment into cancer clinical research programs, with a hope to make them more robust and efficient.
Global Landscape of Cancer Research
Approximately 10 million people die each year due to cancer.{1} Five-year survival rates for certain types of cancers, like lung cancer, are alarmingly low, at around 20%.{2} Moreover, 40% of lung cancers are diagnosed at a late stage.{3} Despite more than 7,459 cancer trials being registered online, 95% of these investigational drugs probably will never see the light of the day.{4,5} Abnormally high mortality rates, late-stage diagnoses, high failure rates of cancer trials, surging demand for oncology services, and staff shortages are some of the key symptoms of a broader issue that needs urgent attention. There’s a pressing need to elevate the resilience and efficiency of cancer research programs. While researchers around the world are trying to address this problem through diverse lenses, it turns out that the outer space or microgravity environment might offer us fertile ground to address these challenges.
Microgravity Environment and Early Experiments
On Earth, gravitational force keeps us anchored as we walk or drive, enhancing our operational efficiency “physically.” However, astronauts don’t have this luxury. As one travels away from Earth this gravitational force greatly subsides, reducing to a mere fraction of what it is on Earth. This is why astronauts are often tethered to their spacecraft with a harness when working outside, to compensate for the near absence of gravity. Hence, this outer space environment where the gravitational force is barely existent is known as the microgravity environment.
To date, numerous experiments have been conducted in this microgravity environment to understand its effects on the human body. Notably, NASA’s Twin Study, which involved two twins—with one remaining on Earth and the other spending 340 days in space—was spearheaded by NASA’s Human Research Program.{6} This study conducted on two genetically similar individuals helped scientists understand the effect of the space environment on the human body and served as the foundation model to expand medical research in space.
Over the past few years, cancer research teams around the world have conducted multiple experiments in this microgravity environment of space to decode its impacts on cancer cells and the results have been astounding.
Tumor Spheroids in Microgravity Environment
Scientists have observed that, in the microgravity environment of space (where gravity is almost non-existent), cancer cells can grow into tumor spheroids that closely resemble those found in the human body on Earth. Replicating this phenomenon in laboratories on Earth, outside the human body, presents a considerable challenge, making it difficult to study these tumor structures in detail. The unique conditions of space allow scientists to overcome this obstacle, as cancer cells in space naturally form three-dimensional structures that can be studied more thoroughly. This discovery has the potential to increase the precision of our oncology research programs here on Earth.
For instance, a research study aboard the International Space Station (ISS) is underway to investigate the pathogenesis of diffuse midline glioma (DMG).{7} This malignancy, emerging from the glial cells within the central nervous system, predominantly manifests in the pons area of the brainstem and primarily targets young children aged 5 to 7. With an alarming 150 to 300 new diagnoses annually and a survival rate of less than 10% two years after diagnosis, the urgency to find better treatments is palpable.{8} This space-based study of DMG cancer cells aims to shed light on their unique properties, leveraging the microgravity environment of the ISS to uncover details about their structure and behavior that could lead to more robust and effective treatments. Beyond DMG, microgravity also plays a crucial role in advancing protein crystallization within oncology research.
KRAS Protein Crystallization in Microgravity
Some 30 to 40% of all cancers originate due to mutations in the KRAS gene. This gene produces proteins involved in the growth and death of cells.{9} Due to mutation in the KRAS gene, the corresponding protein generated by this gene remains in a perpetually active state and doesn’t switch to inactive state periodically as it would if the gene was not mutated. This results in it continuously sending signals that correspond to cell growth, leading to different types of cancers. This phenomenon makes it important for researchers to study the KRAS proteins generated due to mutated KRAS genes so they can develop drugs to block this protein’s action and treat these types of cancer cells.
The challenge is that we cannot fully stabilize the structure of this protein on Earth in the labs, and hence researchers often have a hard time to fully understand the molecular structure and develop corresponding drug-target pairs. This is the problem that the Frederick National Lab for Cancer Research addressed by sending these protein molecules to space with the help of the ISS team.{9} After a predefined interval of time, when a capsule carrying these protein molecules that were crystallized in space returned to Earth, these researchers found that the corresponding crystals formed in space were much more refined, exhibited 50% more orderliness, and the signal-to-noise ratio in them was five times more than similar molecules that were crystallized on Earth. Thus, experiments like this can help us explore the structure of such vital proteins in detail and ensure the next generation of drug-target pairs we develop in oncology are more robust.
Decoding the structure of cancer cells is not the only way microgravity can accelerate the cancer research program on Earth; it can also accelerate their growth and shorten our drug testing cycles.
Accelerated Growth of Cancer Cells in Space
Researchers have observed that cells proliferate at a much faster rate in space than on Earth. A team at Sanford Stem Cell Institute of University of California San Diego observed that when full-blown cancer cells were sent to space in the form of tumor spheroids, their size tripled in just 10 days.{10} This acceleration is attributed to the reduced gravitational forces in space, essentially microgravity. This is astounding because this phenomenon presents an opportunity to test investigational oncology drugs at a pace much faster in a microgravity environment than it might be ever possible here on Earth. This team proved this hypothesis by sending a triple-negative breast cancer tumor organoid to space with an anti-cancer drug. The team concluded that the growth of cancer cells can be reduced at pace much faster in space compared to that on Earth. That brings us to this question: What if we could simulate a microgravity environment here on Earth? Would that yield similar results?
Effect of Simulated Microgravity Environment on Cancer Cells
While there is a need to conduct more experiments in the simulated microgravity environment here on Earth, initial experiments conducted by researchers in Australia seem promising. A research team at University of Technology, Sydney took four different types of cancer cells from different parts of the body—breast, ovary, lungs, and nose—and put them in a simulated microgravity environment here on Earth. What the team found was that in 24 hours, 80% to 90% of these cancer cells died.{11}
While these experiments conducted by cancer research organizations across the world have opened up new avenues to make our cancer research programs more robust and efficient by leveraging the microgravity environment, there is need to develop a standardized framework to address the challenges and risks inherent in this novel approach and to maximize the application of these novel experiments to oncology research programs around the world.
Challenges and Risks
Whether we continue to conduct biomedical oncology research experiments in space or expand our initiatives to include full-fledged cancer clinical trials in space, there are challenges and risks that are yet to be addressed. Transporting cells and equipment to space is not only an extremely capital-intensive endeavor, but also demands intricate planning for each mission. The effect of prolonged exposure to microgravity on our health, DNA, and most importantly immune system is not yet fully clear and needs more research work. These hurdles are further compounded by the limited capacity of the ISS for research activities, the difficulties in managing and transmitting clinical data between Earth and space, and the lack of a standardized framework and governance oversight for translating the findings from oncology experiments in space to Earth. These challenges are summarized below (see Table 1), and will need to be addressed if we are to fully explore the potential of microgravity to advance cancer research here on Earth.
Table 1: Challenges for Conducting Cancer Research Experiments in Space
| Challenge | Overview |
| Financial Constraints | High costs of transporting research equipment and cancer cells to space significantly impact budgeting for oncology experiments. |
| Experiment Design and Logistical Challenges | Designing oncology research experiments that can be conducted in the space environment requires detailed planning that should factor in an array of prerequisites: payload limitations, crew readiness, communication challenges, limitations related to real-time reporting of adverse events, and more. |
| Radiation Exposure Risks | Assessing the effects of space radiation on human health is crucial for the safety and integrity of oncology trials and research experiments conducted in space. |
| Adaptation of Research Protocols | Space-based research may require significant adaptation of Earth-based oncology research protocols to suit the unique conditions of microgravity and radiation exposure. The microgravity environment and spaceflight can result in significant physiological stress and can have significant impacts on cellular and molecular processes. |
| ISS Research Capacity | Limited research capacity on the space station restricts the extent and variety of oncology experiments that can be conducted. |
| Microgravity Health Impacts | The effects of prolonged microgravity on the human body, crucial for understanding cancer progression and treatment efficacy in space, remain largely unknown. |
| Space-Earth Data Communication and Management | Ensuring the efficient management and real-time transmission of clinical data from space to Earth is essential for timely monitoring and responses in research experiments and clinical trials. |
| Trial Design Complexity | Designing oncology trials that can be effectively conducted in the constrained environment of space or that leverage the findings from space requires holistic collaboration of multiple stakeholders from both the oncology and space research community. |
| Participant Recruitment | The feasibility of recruiting suitable participants for space-based oncology trials poses unique challenges, including redefining acceptable health criteria and consent under unusual conditions. |
| Ethical Considerations | Ethical issues are magnified in space research due to increased risks and unknowns, necessitating rigorous review processes and contingency planning for participant safety. |
| Absence of Regulatory Framework | The absence of established frameworks for space-based oncology research has severe impacts on governance, ethical considerations, and procedural standardization. |
| Research Findings Translation | Developing protocols to translate discoveries from space into actionable oncology treatments on Earth is essential for leveraging space research benefits globally. |
Acknowledging the array of challenges and risks inherent in space-based oncology research, the SPACE-ONCO model has been established. This initiative is designed to centralize the results of oncology experiments conducted in space and ensure their widespread dissemination within the global oncology community. These pivotal results are summarized in Table 2 below. Additionally, this aims to provide a structured approach for overcoming unique challenges that oncology research organizations across the world might encounter as they pivot toward leveraging the microgravity environment to advance cancer treatments on Earth. This framework is elaborated in Table 3.
Table 2: Findings from Space-Based Oncology Research Experiments Conducted to Date
| Scope | Findings |
| Tumor Spheroids in Space{7} | ● Microgravity exposure for up to 14 days in space results in the formation of detailed tumor spheroids that mimic the natural growth of cancer cells in the human body on Earth.
● Microgravity in this case serves as an unprecedented platform to study cancer cell interactions, development, dissemination, and response to various treatment modalities. |
| KRAS Protein Crystalliza-tion in Space{9}
|
● Some 30% to 40% of cancers result from mutation in KRAS gene.
● The KRAS gene produces proteins that control the growth and death of cells and mutation in this gene can result in these proteins continuously sending signals of growth to cells which makes them cancerous. ● It’s vital that we have a detailed understanding of the molecular structure of this protein, but on Earth in the labs, it’s hard to stabilize these molecules. ● This same protein molecule in the microgravity environment of space stabilizes much better and resultant crystallizes are more refined, bigger, and offer a signal to noise ratio that is five times better than in those crystallized on Earth. ● This makes it easier for research groups to study this protein in detail, develop drug-target pairs that are more robust and effective, and thus accelerate our ability to develop effective cancer drugs here on Earth. |
| Accelerated Growth of Cancer Cells in Space{10}
|
● Normal stem cells present in our blood switch between “sleep” and “active” states and remain in “sleep” state for 80% of the time.
● If they remain in an active state for a longer time, the stem cells age faster and lose their ability to clone and make blood. This happens often when our body is under stress. ● It is observed that stem cells age faster in microgravity than on Earth. ● Similarly, cancer cell tumor spheroids, when introduced in the microgravity environment, triple in size in just 10 days. ● When these same triple-negative breast cancer tumor spheroids were sent to space with anti-cancer drug, their growth was reduced at pace faster than on Earth. |
| Effect of Simulated Micrograv-ity Environ-ment on Cancer Cells{11} | ● Researchers took cancer cells from different parts of the body—breast, ovary, lungs, and nose—and put them in a simulated microgravity environment here on Earth.
● They found that in 24 hours, 80% to 90% of these cells were dead. ● There is more research work needed on this front, but the initial results suggest new avenues to conduct oncology research experiments in simulated microgravity environments on Earth. |
SPACE-ONCO Framework: Holistic and Responsible Integration of Microgravity Environment in Cancer Clinical Research Programs
This framework (see Figure 1 and Table 3) is meticulously designed to navigate the unique challenges and opportunities presented by conducting oncology research in space, aiming directly at the needs and interests of oncologists and the clinical research community. It outlines a series of structured steps, each accompanied by actionable items, intended to facilitate the translation of space-based research findings into practical, Earth-bound clinical applications.
By establishing collaborations with regulatory bodies, securing essential funding, adapting research protocols for the space environment, and ensuring the ethical recruitment and safety of participants, this framework provides a comprehensive roadmap for pioneering oncology experiments beyond our planet.
The focus on mitigating radiation exposure, leveraging the ISS’s research capacity, and understanding microgravity’s impact on health highlights the framework’s commitment to pushing the boundaries of current cancer treatment modalities and knowledge.
Moreover, the framework emphasizes the importance of effective data management between Earth and space, innovative trial design, and the translation of research findings to enhance clinical oncology practice. By advocating for a collaborative approach that involves key partnerships with space agencies, aerospace engineers, and the broader oncology research network, the framework aims to harness the unique aspects of the space environment to advance cancer treatments.
For oncologists and clinical researchers, this represents an exciting frontier of exploration that promises to yield new insights into cancer biology, potentially leading to breakthroughs in therapy and patient care.
Through dedicated communication channels, training in space-specific data management systems, and a focus on the practical application of research findings, the framework seeks to integrate space-based research into the fabric of oncology, enriching the field with novel perspectives and tools to combat cancer.
Figure 1: SPACE-ONCO Framework—Microgravity-Enabled Cancer Clinical Research Program
Table 3: SPACE-ONCO Framework for Responsible and Holistic Integration of Microgravity Environment in Cancer Clinical Research Programs
| Pillar | Overview |
| Develop Regulatory and Ethical Framework | ● Engage with space and health regulatory bodies to ensure compliance with both space research and clinical trial regulations.
● Formulate ethical guidelines that specifically address patient consent and safety within the unique confines of space research. ● Create a multidisciplinary oversight board including oncologists and space scientists, to review and adapt regulations and guidelines as space-based oncology research evolves. |
| Secure Funding and Manage Budget | ● Seek collaborative funding opportunities with organizations interested in the intersection of space research and oncology, including cancer research foundations and space agencies.
● Propose joint funding applications with aerospace companies focusing on health research in space, highlighting the potential for groundbreaking discoveries in oncology. ● Organize a consortium of oncology research institutions to pool resources and share the financial burden of space-based research projects. ● Ensure this consortium provides equitable access to space-based research programs and resources for countries across the world irrespective of their demographics, economic strength, or capabilities. |
| Adapt Oncology Research Protocols for Space | ● Define clinical research protocols that address the unique aspects of microgravity and radiation on cancer biology.
● Initiate pilot studies on Earth that simulate aspects of the space environment, such as radiation and microgravity, to refine protocols before space implementation. ● Establish a task force of oncologists and space scientists to continuously review and update research protocols based on the latest scientific discoveries. |
| Design Holistic Oncology Research Experiments | ● Design oncology experiments that are not only feasible in space, but which also yield results with clear implications for Earth-based clinical practice.
● Work closely with aerospace engineers to ensure experiment hardware is optimized for space conditions while meeting clinical research standards. ● Develop a comprehensive logistics plan that includes contingencies for experiment adaptation based on real-time data and findings. ● Explore the integration of robotics and automation to streamline the challenges associated with transporting samples to and from space research labs. |
| Mitigate Radiation Exposure Risks | ● Conduct joint research with radiation oncologists and physicists to develop innovative radiation shielding techniques relevant to both space and terrestrial oncology settings.
● Integrate advanced biomonitoring systems into research protocols to assess the real-time impact of space radiation on cellular and molecular processes. ● Share findings with the wider oncology community to enhance understanding of radiation’s effects on cancer and normal tissues, potentially informing radiotherapy approaches. |
| Optimize Use of ISS Research Capacity | ● Advocate for dedicated oncology research slots on the ISS through collaborations with space agencies, emphasizing the potential for significant advancements in cancer treatment.
● Foster partnerships with existing ISS research projects to explore synergies and shared use of equipment and facilities, maximizing the impact of each experiment. ● Organize a space oncology research network to streamline proposals, share results, and coordinate access to the ISS and other space research platforms. |
| Understand and Study Impact of Microgravity on Health | ● Prioritize the study of microgravity’s effects on tumor growth and metastasis, involving collaborations between space biologists and clinical oncologists.
● Share microgravity research findings at oncology conferences and in clinical journals, highlighting their relevance to understanding cancer progression and treatment resistance. ● Utilize Earth-based microgravity analogs (i.e., complementary studies to replicate space study results, validating their applicability to clinical oncology). |
| Implement Robust Clinical Data Communication and Management Systems | ● Develop secure, efficient data management systems that allow for seamless integration of space-based research data into Earth-based clinical databases.
● Train research teams in the utilization of these systems to ensure high-quality data collection, analysis, and real-time decision-making. ● Share best practices and systems architecture with the broader oncology research community to facilitate the adoption of space-based oncology research methodologies. |
| Tailor Clinical Trial Designs to Accommodate Space Environment | ● Leverage the unique environment of space to conduct cancer clinical trials that could benefit from microgravity conditions, such as novel drug delivery systems.
● Collaborate with clinical trial specialists to design space-compatible trials that can yield results directly translatable to terrestrial setups. ● Share trial designs and outcomes with the oncology community through dedicated workshops and publications focused on space research’s clinical applications. |
| Recruit Participants and Ensure Safety | ● Create clear, comprehensive recruitment and informed consent processes that address the unique aspects and risks of space-based research, ensuring participants are well-informed.
● Implement strict safety protocols, closely monitored by a dedicated team of oncologists and space medicine experts, to oversee participant well-being. ● Develop an international registry of space research participants to monitor long-term health outcomes and contribute to a broader understanding of space’s impact on human health. |
| Translate Research Findings from Both Space-Based Research Programs and Clinical Trials for Earth-Based Applications | ● Establish a dedicated translation committee and protocol to evaluate space-based research findings for their direct applicability to clinical oncology, focusing on rapid implementation.
● Ensure this protocol and committee factor the physiological stress and other impacts induced due to space-based research on cellular and molecular processes into these translations. ● Implement post-treatment health evaluation programs to study recurrence of oncology symptoms or condition (if any) and optimize the oncology research protocol developed for microgravity environment to address this challenge and minimize the recurrence of cancer in such patients. ● Foster collaborations between research institutions, hospitals, and the pharmaceutical industry to expedite the development of treatments based on space research discoveries. ● Organize annual forums that bring together space researchers and the oncology community to discuss the latest findings and their implications for cancer treatment. |
By focusing on these core areas, providing a structured approach, and promoting interdisciplinary collaboration, this framework aims to make space-based oncology research a key component of future cancer clinical research programs, ensuring resilience, efficiency, and patient-centered ouctomes.
References
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Deepika Khedekar, MPharm, (deepika.khedekar@gmail.com) is a Centralized Clinical Lead with IQVIA Inc., Mumbai, India.
