At the American Association for Cancer Research meeting in April 2016, then Vice President of the United States, Joe Biden, revealed the Cancer Moonshot℠ initiative— a program with the goals of accelerating scientific discovery in cancer research, fostering greater collaboration among researchers, and improving the sharing of data (1,2). The Cancer Moonshot is part of the 21st Century Cures Act, which earmarked $1.8 billion for cancer-related initiatives over 7 years. The National Cancer Institute (NCI) and the Cancer Moonshot program have supported over 70 programs and consortia, and more than 250 research projects. According to the NCI, the initiative from 2017 to 2021 resulted in over 2,000 publications, 49 clinical trials and more than 30 patent filings. Additionally, the launch of trials.cancer.gov has made information about all cancer research trials accessible to anyone who needs it (3).
“We will build a future where the word ‘cancer’ loses its power.”
First Lady, Dr. Jill Biden
In February 2022, the Biden White House announced a plan to “supercharge the Cancer Moonshot as an essential effort of the Biden-Harris administration” (4). Biden noted in his address that, in the 25 years following the Nixon administration’s enactment of the National Cancer Act in 1971, significant strides were made in understanding cancer. It is now recognized not as a single disease, but as a collection comprising over 200 distinct diseases. This period also saw the development of new therapies and enhancements in diagnosis. However, despite a reduction in the cancer death rate by more than 25% over the past 25 years, cancer continues to be the second leading cause of death in the United States [4].
The Cancer Moonshot is a holistic attempt to improve access to information, support and patient experiences, while fostering the development of new therapeutics and research approaches to studying cancer. In this article, we will focus on research, diagnostics and drug discovery developments.
Solving for Undruggable Targets
KRAS , a member of the RAS family, has long been described as “undruggable” in large part because it is a small protein with a smooth surface that does not present many places for small molecule drugs to bind. The KRAS protein acts like an off/on switch depending upon whether it has GDP or GTP bound. KRAS mutations are associated with many cancers including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC). The G12 position in the protein is the most commonly mutated; G12C accounts for 13% of the mutations at this site, and is the predominant substitution found in NSCLC, while G12D is prevalent in PDAC (5).
In 2021, the FDA gave accelerated approval of the first small molecule inhibitor of the KRAS-G12C protein, sotorasib, for non-small-cell lung cancer (NSCLC) (6). A second KRAS-G12C inhibitor, adagrasib, has also been developed and approved (5). In 2023, an inhibitor of the KRAS-G12D protein, MRTX1133, was described and showed promise in pancreatic cancer model systems (7). These inhibitors were noted to induce changes in the tumor microenvironment that included a proinflammatory environment and the activation of T cells (5,7). For MRTX1133, T cells were shown to be necessary for the inhibitor’s antitumor effects (7).
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Understanding the Role of the Tumor Microenvironment in Cancer Treatment
Pancreatic cancer makes up only 3.2% of all yearly new cancer cases in the United States but is the third most common cause of cancer deaths each year. Tumor cells cause significant changes in the area that surrounds them, the “tumor microenvironment” (TME). The TME includes blood vessels, connective tissues and extracellular matrices, immune cells, and other components. Understanding how the tumor microenvironment affects the success of cancer treatments, and the development of drug resistance is a focus of the Pancreatic Cancer Microenvironment Network (PaCMEN; 3,8).
A study published by Strommes et al. (9) looked at engineered T cells that had been introduced into PDAC to see if they could regain some of their anti-tumor activity in the presences of PD-1 immune checkpoint inhibitors. The researchers found that the TME was immunosuppressive, and therefore engineered T cells that initially showed antitumor activity lost that ability. Furthermore, introducing immune therapies such as PD-1/PD-L1 inhibitors did not restore their activity. Additionally, when the engineered T cells were further characterized, their molecular profile did not match that of either naïve or effector T cells, but rather they were similar in profile to naturally exhausted T cells. This is one of the ways the TME can influence the effectiveness of immunotherapies in pancreatic cancers .
“This is one of the truly bipartisan issues in the United States Congress…This can really be an American moment…that proves to ourselves and quite frankly to the world that we can do really big things.”
President Joe Biden, February 2, 2022
Summary
We’ve showcased just a few of the many innovative projects from the Cancer Moonshot—each demonstrating how modern science and technology are transforming cancer treatment. In an era marked by rapid technological advances, such as using artificial intelligence to discover new drugs, the Cancer Moonshot stands out. It reminds us of President John F. Kennedy’s call to action: “We do these things not because they are easy, but because they are hard.” This initiative isn’t just leveraging advanced technology; it’s also forging global collaborations to tackle one of the toughest challenges in healthcare—cancer. By bringing together the best minds from around the world, the Cancer Moonshot serves as a model for solving complex global problems.
References
- Transcript of Vice President Joe Biden’s Address to American Association of Cancer Researchers 2016 [Internet https://medium.com/@VPOTUS/here-s-what-the-vice-president-said-to-the-largest-convening-of-cancer-researchers-in-the-country-3007bb196dbd#.yiipgrueh Accessed: May, 10, 2016]
- Sharpless, N.E. and Singer, D.S. (2021) Progress and Potential: The Cancer Moonshot. Cancer Cell. May 6. https://www.sciencedirect.com/science/article/pii/S1535610821002233?via%3Dihub
- National Cancer Institute. Cancer Moonshot Progress. https://www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative/progress [Internet. Accessed May 3, 2024]
- The President and First Lady’s Cancer Moonshot: Ending Cancer as We Know It. The White House. https://www.whitehouse.gov/cancermoonshot/
- Liu, J., Kang, R. and Tang, D. (2022) The KRAS-G12C inhibitor: Activity and Resistance. Cancer Gene Therapy 29, 875–8.
- National Cancer Institute (2021) FDA Approval of KRAS Inhibitor Sotorasib for Lung Cancer Hailed as a Milestone. [Internet: https://www.cancer.gov/news-events/cancer-currents-blog/2021/fda-sotorasib-lung-cancer-kras Accessed May 8, 2024].
- Kemp, S.B. et al. (2023) Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer. Cancer Discov. 13(2): 298–311.
- PaCMEN (Pancreatic Microenvironment Network) [Internet: https://www.pacmen.org/ Accessed: May 10, 2024]
- Stromnes, I.M. et al. (2022) Insufficiency of compound immune checkpoint blockade to overcome engineered T cell exhaustion in pancreatic cancer. J. Immunother Cancer 10(2): e003525
Michele Arduengo
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