The Pre-Cancer Atlas may provide opportunities to detect cancer early and intercept cancer at premalignant stages.
The cancer research community is hindered by a lack of comprehensive, multidimensional data linking spatial and temporal information about various malignancies as they transition from precancers to cancerous tumors and later metastasize, eventually developing therapeutic resistance. Now, the Human Tumor Atlas Network (HTAN), a large-scale, collaborative effort employing a combination of robust, established approaches, such as histologic staining and electron microscopy, with cutting-edge methods, including single-cell techniques, aims to address this dearth of information by constructing three-dimensional molecular, spatiomolecular, histologic, and anatomic maps of human cancers as they progress.
In an interview for Cancer Prevention Research, HTAN investigator Avrum Spira, MD, MS, Professor of Medicine, Pathology and Bioinformatics at Boston University (Boston, MA) and Global Head, Lung Cancer Initiative at Johnson & Johnson, shared his thoughts on the project with Cancer Prevention Research editor-in-chief Raymond DuBois, MD, PhD, Dean of the College of Medicine and Director of the Hollings Cancer Center at the Medical University of South Carolina (Charleston, SC).
What is the HTAN and how does it differ from prior efforts?
The HTAN is part of the NCI Cancer Moonshot Initiative. Participating researchers plan to establish the clinical, experimental, computational, and organizational framework needed to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. The results from these efforts are expected to have a profound impact on the understanding of cancer biology and offer the opportunity to improve early cancer detection, prevention, and precision medicine treatments for patients with cancer and those at higher risk for cancer (Rozenblatt-Rosen et al. Cell https://doi.org/10.1016/j.cell.2020.03.053; 2020).
HTAN atlases should help reveal translational aspects of malignancy that could not be fully addressed by previous large-scale cancer genomics programs, such as The Cancer Genome Atlas. Information regarding the tumor microenvironment and its myriad cellular interactions is accessible to the HTAN through spatial and single-cell approaches and may propel the development of remarkable targeting opportunities for therapy.
Also, most previous efforts have focused on primary tumors with limited treatment and outcome data, whereas the HTAN emphasizes longitudinal sampling, including samples from precancers, advanced tumors, metastases, and tumors as they respond to treatment, alongside collection of comprehensive clinical data. Collectively, this work will inform detection, prevention, and treatment strategies.
Finally, the integration of spatial methods will help link cancer genomics and histopathology, the two primary means of diagnosing cancer and informing therapy. As a result, there is promise that predictive biomarkers based on the HTAN's integrative, multimodal analyses could outperform genetic or histologic biomarkers alone.
What is the Pre-Cancer Atlas project and how are you involved in it?
The Pre-Cancer Atlas project is a key component of the NCI's HTAN that focuses on developing a spatial and temporal atlas of the molecular and cellular changes that characterize premalignant diseases across a number of different tumor types. The concept of developing such an atlas was initiated more than 5 years ago by the NCI through its Early Detection Research Network, which I was fortunate to be involved with, followed by an NCI-funded pilot study that I co-led within its Molecular and Cellular Characterization of Screen-Detected Lesions consortium. Within the last 2 years, momentum for developing this Pre-Cancer Atlas has increased dramatically because of the HTAN Moonshot funding mechanism. Five groups have been funded to participate in this premalignant work across multiple tumor types, and I have been privileged to co-lead one of them in lung cancer alongside Dr. Steven Dubinett (University of California, Berkeley, CA).
What breakthroughs have been made through this project and which are you most excited about?
I am very excited about a number of breakthroughs in this space. On the technical side, there have been recent advances that allow us to collect and analyze smaller and smaller amounts of tissue containing premalignant lesions in multiple organs, and there has been a revolution in the molecular biology techniques required to characterize the molecular alterations in these types of specimens at a single-cell resolution.
On the scientific side, while still relatively early days, there have been a number of key discoveries on the genomic alterations present in premalignant lesions, as well as changes in the immune microenvironment of those lesions. These discoveries can directly provide us with molecular biomarkers for distinguishing indolent versus aggressive premalignant lesions, as well as novel targets for intercepting those lesions at highest risk for progressing to invasive cancer. As an example, one of our recent studies (Beane JE, et al. Nat Commun https://doi.org/10.1038/s41467-019-09834-2; 2019.) profiled the transcriptome of bronchial premalignant lesions, which are precursors of lung squamous cell carcinoma that have variable outcomes in terms of progression to invasive cancer. We have discovered an important role for the immune microenvironment as an indicator of premalignant disease progression and have identified possible targets for lung cancer interception. The concept that the immune microenvironment may be an important determinant of premalignant disease outcome, just as it is in some late-stage cancers, could provide a real opportunity to prevent progression.
On the clinical side, I am very excited about the emerging partnerships between academia and industry to translate findings from the Pre-Cancer Atlas into the clinic. Most oncology work on the pharmaceutical industry side has traditionally been focused on later stages of cancer because of the feasibility of and timeline for completing those types of clinical trials. Now, companies such as Johnson & Johnson and small biotechnology groups are investing in longer and more challenging studies of earlier disease stages, including premalignancy. Given the biological and genomic complexity of later stage cancer, targeting earlier stages of the disease holds the promise of even greater efficacy and less resistance to therapeutic interventions.
Ultimately, what excites me most is the potential for the Pre-Cancer Atlas to help in the development of less invasive ways to detect cancer early, potentially at a premalignant state, and combine that with industry partnerships to intervene earlier and launch clinical trials in this setting. In my mind, that is what makes this the right time to be compiling a pre-cancer atlas: you can deploy robust technology that has not been available before and have emerging partners who can translate the results into patient benefit.
What are the highest priorities for the future of cancer prevention research?
The Pre-Cancer Atlas is a foundational piece of the future of cancer prevention research. What is needed next is a cancer prevention and interception moonshot feeding on the data and insights derived from the Pre-Cancer Atlas. For those insights to be translated into novel interventions, a coalition of stakeholders, including federal agencies, foundations, and industry, will be needed to design and execute on the complicated clinical development pathway for cancer interception trials, including defining regulatory endpoints for those studies. Importantly, preclinical models have always been a challenge for studying premalignant disease, so we will need better animal models and better in vitro models in which we can test hypotheses that come out of the Pre-Cancer Atlas before committing to long complex clinical trials.
Early detection will remain a critical component of the future of cancer prevention. Insights from the Pre-Cancer Atlas will provide novel early-detection markers to measure in less invasive biosamples. Pan-cancer screening with a blood test may be within reach in the near future. Artificial intelligence and machine-learning algorithms applied to imaging studies hold the promise to transform early detection of many cancer types. Ultimately, it will be the integration of clinical, radiomic, and molecular tests that will unlock our full potential for early detection.
What impact has COVID-19 had on your progress?
COVID-19 has, to some extent, impacted our progress. The collection of specimens from patients with precancers has been limited in the last 6 months because many academic medical centers included as study sites have slowed down or stopped these types of clinical studies. As academic medical centers have recently started to reopen on the research front, we are seeing an increase in our ability to perform molecular studies on samples that are collected. The good news is that computational analysis of the data has not been impacted by the pandemic and we have been able to double down on our efforts to analyze the data from previously collected samples.
Interestingly, we have been able to pivot and look at some of our molecular data to gain biological insights on COVID-19. Given that SARS-CoV-2 is a respiratory tract pathogen and that we are studying airway and lung tissue samples within our pre-cancer atlas, we can look at some of the molecular data from these samples to get a better understanding of how we might target COVID-19. As one example, we have gained some insights on the potential relationship between cigarette smoking and the ACE2 receptor in upper and lower airway epithelium, a critical entry point for the coronavirus to infect respiratory epithelial cells. This may help explain why smokers are more susceptible to infection.
One of the silver linings from this pandemic is that we are learning what is possible from a translational science perspective when all stakeholders work together with urgency. I am inspired after seeing government agencies, foundations, academia, and industry working together on COVID-19 to advance the science and its translation into vaccines and therapeutics at an unprecedented pace. What if we could bring this same mindset and urgency to cancer interception and prevention?
Is there anything else about this area you would like to highlight?
I have never been more excited about the opportunity we now have to prevent cancer. There are a number of opportunities in alignment, including advances in the science and technology for early cancer detection and emerging biological insights from the Pre-Cancer Atlas. I feel we are at a tipping point, and by being in both industry and academia, I can see the compelling opportunity for us to intervene at a much earlier stage of disease. Where we are in our current health system, focusing on very late stages of disease, is simply not sustainable or as effective as needed. We must move to treating cancer earlier and intercepting those incubating a precancer process by understanding the earliest cellular and molecular changes in cancer development. I am confident that the next 5–10 years will be some of the most exciting times in the history of cancer prevention research.
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