Testing Novel Cancer Agents Beyond the Final Frontier

‘Space: The final frontier … To Boldly Go Where No One Has Gone Before…’ * This famous opening narrative of the iconic ‘Star Trek’ television series, outline the central theme of the science fiction series: exploring the unknown in search of new knowledge.

Now scientists at the University of California San Diego Sanford Stem Cell Institute, are among the first to test innovative cancer agents in space. Using a private astronaut mission, the scientists launched several new nanobioreactor experiments onto the International Space Station (ISS) via the second Axiom Space Private Astronaut Mission (PAM)** known as Axiom Mission 2 (Ax-2).

These latest experiments expand their research on human stem cell aging, inflammation and explore leukemia, breast cancer and colorectal cancer in low Earth orbit. The experiments are also designed to monitor astronauts’ stem cell health over time.

Cancer in Low Earth Orbit
Increasing evidence shows that microgravity conditions can accelerate aging, inflammation and immune dysfunction in human stem cells. Understanding this process is not only helpful for keeping astronauts healthy — it could also teach us how to better treat cancer on Earth.

During the Axiom Space’s first Private Astronaut Mission, known as Axiom Mission 1 or Ax-1, conducted under the NASA-funded Integrated Space Stem Cell Orbital Research (ISSCOR-) program, researchers from UC San Diego sent blood stem cells aboard the ISS across four launches and found that several pre-cancerous markers were elevated after one month in space. The results demonstrated that in low Earth orbit, cancer stem cells appeared to regenerate more easily and become more resistant to standard therapies. Of particular note was the activation of APOBEC3C, a deoxyribonucleic acid (DNA) editing enzyme that deaminates cytosine bases to uracil bases, which are then converted to thymine bases in DNA, and ADAR1 (adenosine deaminase acting on RNA 1), a ribonucleic acid (RNA) editing enzyme that deaminates adenosine bases to inosine, which are then converted to guanine bases in DNA are two enzymes that edit DNA and RNA, respectively, and promote cancer proliferation and immune evasion.[1][2][3]

Building on these original results, the Ax-2 mission will help determine if two inhibitory drugs can reverse the regeneration in an organoid model of breast cancer, allowing researchers to further explore these initial findings during the Ax-2 mission, which is led by Catriona Jamieson, MD, Ph.D., professor at UC San Diego School of Medicine, Koman Family Presidential Endowed Chair in Cancer Research at UC San Diego Health and director of the Sanford Stem Cell Institute. and her collaborators Sheldon Morris, MD, Ph.D., and Ludmil Alexandrov, Ph.D., both associate professors at UC San Diego School of Medicine.

In the latest launch, the scientists have sent tumor organoid models of leukemia, colorectal and breast cancer into low Earth orbit, where the microgravity conditions will accelerate insights into how cancers adopt stem cell properties that make them resistant to standard therapy, including dormancy, regeneration and longevity.

The researchers will also test two ADAR1 inhibitors, Fedratinib (InrebicI®; Impact Biomedicines, a Bristol-Myers Squibb Company) and Rebecsinib (17S-FD-895; Aspera Biomedicines)***, to see if the drugs can reverse the process of malignant regeneration and potentially prevent cancer progression. These experiments mark the start of a developing program at the Sanford Stem Cell Institute to expand stem cell translational research and drug discovery in space.

Space Hematopoietic Stem Cell Aging
A second longitudinal study are designed to monitor the health of astronauts’ stem cells over time – during and after each mission**** – to evaluate the effects of spaceflight on stem cell aging, immune function and cancer stem cell generation.

Blood samples will be collected from the crew members before, during and immediately after the mission, with up to five years of annual follow-ups after the trip.

The scientists will assess the activity of DNA and RNA-editing enzymes such as APOBEC3C and ADAR1 in the blood stem cells and cancer organoids. Dysregulation of these enzymes has been linked to immune dysfunction and potential pre-cancer changes, so understanding when and how they become perturbed in the astronauts will allow researchers to develop potential countermeasures.

“Space is a uniquely stressful environment,” noted Jamieson.

“By conducting these experiments in low Earth orbit, we are able to understand mechanisms of cancer evolution in a compressed time frame and inform the development of new cancer stem cell inhibitory strategies,” she added.

Integrated Space Stem Cell Orbital Research
These projects are part of the NASA-funded Integrated Space Stem Cell Orbital Research (ISSCOR) Center, a collaboration between UC San Diego Sanford Stem Cell Institute, JM Foundation and Axiom Space. The experiments will take place over 10 days in orbit, with subsequent data collection and analysis performed at UC San Diego.

The findings will inform the development of predictive models for cancer and immune dysfunction-related diseases and could lead to the development of new drugs to prevent or treat these conditions during space exploration and here on Earth.

“We are pleased to have the opportunity with our private astronaut missions to advance this important work, aligned with the White House Cancer Moonshot initiatives,” explained Christian Maender, executive vice president of in-space solutions at Axiom Space.

“Our mission is to improve life on Earth and foster the possibilities beyond by building and operating the world’s first commercial space station. Together with the Sanford Stem Cell Institute team, we are building history,” Maender added.

“With the growing support of NASA, philanthropic funders and our partners in commercial spaceflight, this is just the beginning of a long line of exciting and impactful health science advances that will be enabled by space,” Jamieson concluded.

Note: * The wording of the original 1960s show was updated in the 1990s Star Trek: The Next Generation from ‘no man’ to ‘no one.’

** PAMs are privately funded, fully commercial flights to the International Space Station on a commercial launch vehicle that are dedicated to commercial research, outreach, or approved commercial and marketing activities.
*** Rebecsinib, also known as 17S-FD-895, is a novel selective splicing modulator that inhibits both ADAR1-mediated immune silencing and pro-survival MCL1-L expression that collectively drive therapy resistant cancer stem cell generation in a broad array of malignancies.
**** Known as SASHA (Ax-2) – Space Hematopoietic Stem Cell Aging (Ax-2) on the Axiom-2 (Ax-2) private astronaut mission (PAM) evaluates DNA- and RNA-editing enzymes that are related to the development of inflammatory disease and cancer.

Highlights of prescribing information
Fedratinib (InrebicI®; Impact Biomedicines, a Bristol-Myers Squibb Company) [Prescribing information]

Reference
[1] Qian Y, Gong Y, Zou X, Liu Y, Chen Y, Wang R, Dai Z, Tasiheng Y, Lin X, Wang X, Luo G, Yu X, Cheng H, Liu C. Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma. Oncogenesis. 2022 Jun 24;11(1):35. doi: 10.1038/s41389-022-00411-9. PMID: 35750693; PMCID: PMC9232547.
[2] Constantin D, Dubuis G, Conde-Rubio MDC, Widmann C. APOBEC3C, a nucleolar protein induced by genotoxins, is excluded from DNA damage sites. FEBS J. 2022 Feb;289(3):808-831. doi: 10.1111/febs.16202. Epub 2021 Oct 4. PMID: 34528388; PMCID: PMC9292673.
[3] Baker AR, Slack FJ. ADAR1 and its implications in cancer development and treatment. Trends Genet. 2022 Aug;38(8):821-830. doi: 10.1016/j.tig.2022.03.013. Epub 2022 Apr 19. PMID: 35459560; PMCID: PMC9283316.
[4] Erdmann EA, Mahapatra A, Mukherjee P, Yang B, Hundley HA. To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis. Crit Rev Biochem Mol Biol. 2021 Feb;56(1):54-87. doi: 10.1080/10409238.2020.1856768. Epub 2020 Dec 27. PMID: 33356612; PMCID: PMC8019592.

Featured image by NASA on Unsplash. Used with permission.