Pradip De MS PhD, Fred Ashbury, PhD, MACE
Cancer is initially considered to be an exclusively genetic disease. This perspective, while at one time an important break from previous thinking on how cancers develop, is now known to be too narrow. The interplay of deregulated genetics, epigenetic mechanisms that change the regulation of gene expression, and microbiota are each now known to contribute to the cancer phenotype. “Cancers, we have discovered, are situated into our genome” (1). Indeed, cancer usually arises from a person’s gene(s) when the disease is inherited, but that only occurs for about one cancer in ten (2)
In most cases, gene aberrations/mutations accumulating over a lifetime can also facilitate cancer development by affecting the structure and function of the genome. The accumulation of alterations may arise from various mechanisms, and epigenetics alone create a broad landscape to explore. Epigenetic alterations are not only a mechanism for developing cancer, but they also play a key role in drug response. For example, mismatch repair deficient (MMRd) cancers responded very well to the FDA-approved checkpoint inhibitor pembrolizumab (3, 4). A recent article by Chow RD et al. (5) showed from their clinical trial study (NCT02899739) that patients with genomic mutational MMRd tumors had significantly higher response rates (ORR: 100%) and longer survival than those with epigenetic MMRd tumors (ORR;44%). These data indicate important differences in the basic immunological mechanisms between loss-of-function mutation or copy number loss of MMR genes and epigenetic silencing of those genes.
Besides epigenetic changes to DNA, modification of RNA can also play a significant role in cancer. As Esteller and colleagues wrote in a recent review article, chemical modifications of RNA molecules- the so-called “epi transcriptome” - have been found to regulate various aspects of RNA functions, including protein synthesis (6). The critical question is: how can we manufacture targeted therapies that not only stop the alteration of the chromatic structure of cancer cells but also reprogram cancer cells to return to a healthy/non-cancerous state? Another question is whether we know enough about the epigenome of the tumor microenvironment (TME) since TME plays a critical role in cancer progression and management of the disease(7).
Besides epigenetics, the microbiome is another essential aspect that needs to be considered during cancer progression. The human microbiome is now considered our “last organ” (8). Promising results from microbiome research also boosted the “microbiome market” and private investment in companies and startups (www.global-engage.com).
Since infectious diseases have affected human populations throughout most of history, medical microbiology is the earliest focus of research and public interest. Antonie van Leeuwenhoek investigated diverse bacteria of various shapes, fungi, and protozoa called “animalcules,” mainly from water, mud, and dental plaque samples as a first indication of microorganisms interacting with complex communities. Robert Koch’s explanation of the origin of human and animal diseases as a consequence of microbial infection, and the development of the pathophysiological-concept was an essential milestone in microbiology (9). The history of microbiome research from the seventieth century until our modern days highlights the shift of the paradigm from microbes as unsocial organisms causing diseases to the holistic view of microorganisms being the center of the One Health Concept: positively interconnecting all areas of our lives (10). The microbiota comprises all living members forming the microbiome (bacteria, archaea, fungi, algae). And microbiome consists of microbiota and their “theatre of activity” (structural elements, like protein, lipid, metabolites/signal molecules, and also surrounding environmental conditions) (10). In cancer patients, tumor-associated microbiota plays a crucial role in cancer progression, metastasis, immune surveillance, and drug resistance. Recently, published single-cell RNA sequencing in oral squamous cell carcinoma and colorectal cancer demonstrated the distribution of intratumoral microbiota varies within the patient in a specific way. Furthermore, the presence of bacteria led to significant upregulation of specific gene expressions and signaling pathways related to cancer progression (11). It has been known that gut microbiota has been implicated in cancer and shown to modulate anti-cancer drug efficacy, including immunotherapy. Preclinical mouse models of sarcoma, melanoma, and colon cancer showed that the optimal responses to anti-CTLA4 and anti-PD-L1 depend on the presence of specific species of commensal bacteria in the gut, showing the association between microbiome and response to immunotherapy (11, 12). A more comprehensive understanding of the functions of distributions of microbiota in host pathophysiology and cancer treatment is critical to developing personalized medicine that enhances cancer management by modulating gut microbial compositions and functions. Having said that, a person’s gut microbiome constantly changes, and one sample does not provide an accurate picture of a rapidly evolving ecosystem. Hence, the tests are not a diagnostic tool, even in the NCI cancer centers. On the other hand, epigenetics represent an untapped opportunity in cancer biology for researchers, oncologists, and tomorrow’s patients living with cancer. The active engagement of community oncology practices with academic partners helps meet these challenges; community/academic alliances result in improved cancer patient care and provider efficacy.
OK, so the big question is, what can the community oncologist do with what has been described above? When contemplating treatment for a patient with selected gene alterations, what information can I get about the epigenetic mechanisms and about microbiota to help me decide what to do? Are there tests? Has the literature suggested that a patient with a diagnosis of specific cancer with X gene + Y epigenetic profile + Z microbiota profile requires a different treatment protocol than another patient, and how do I know this to alter the treatment? Answers to these questions are critical to take the next step in improving therapy selection and patient outcomes.
References
1. Mukherjee S. The Emperor of All Maladies: A Biography of Cancer: Scribner; 2010. The Genetics of Cancer 2022 [updated August 17th 2022.
2. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509-20.
3. Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020;383(23):2207-18.
4. Chow RD, Michaels T, Bellone S, Hartwich TMP, Bonazzoli E, Iwasaki A, et al. Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti-PD-1 Immunotherapy in Endometrial Carcinoma. Cancer Discov. 2023;13(2):312-31.
5. Esteller M, Pandolfi PP. The Epitranscriptome of Noncoding RNAs in Cancer. Cancer Discov. 2017;7(4):359-68.
6. Sulaiman R, De P, Aske JC, Lin X, Dale A, Gaster K, et al. Characterization and Clinical Relevance of Endometrial CAFs: Correlation between Post-Surgery Event and Resistance to Drugs. Int J Mol Sci. 2023;24(7).
7. Berg G, Rybakova D, Fischer D, Cernava T, Verges MC, Charles T, et al. Microbiome definition re-visited: old concepts and new challenges. Microbiome. 2020;8(1):103.
8. Mulherjee S. The Song of the Cell: An Exploration of Medicine and the New Human: Scribner; 2022.
9. Galeano Nino JL, Wu H, LaCourse KD, Kempchinsky AG, Baryiames A, Barber B, et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. 2022;611(7937):810-7.
10. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084-9.
11. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-84.
12. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-84.
Fredrick D. Ashbury, PhD
Chief Scientific Officer, VieCure Professor (Adj), Department of Oncology University of Calgary Professor (Adj), DLSPH, University of Toronto
Pradip De, PhD
Signal Transduction Pathway Consultant, VieCure, Assistant Professor, Department of Internal Medicine at the University of South Dakota, South Dakota, USA