Overcoming cancer and aging without killing cells?
All current anti-cancer therapy commonly aims to kill cancer cells. Despite significant advances in anti-cancer therapy, cancer remains one of the most threatening and incurable disease due to its recurrence and side effects caused by competitive release and normal cell death. Senolytics, killing senescent or aged cells, have similar side effects as anti-cancer therapy.
Biorevert suggests a solution.
Historically, there have been observations of biological phenomena of cancer or aged cells being transformed into normal-like or young healthy cells. In 1907, malignant teratoma in mouse ovary was first observed to differentiate into normal cells under certain conditions. Since then, there have been various reports elucidating cancer cells reverted to normal cells by manipulating their surrounding microenvironment or providing specific stimulations.
In aging, a study reported that partial reprogramming with OSKM (Oct4, Sox2, Klf4, c-Myc) expression not only eliminated the phenotypic markers of cellular aging in mice and human cells but also extended lifespan with improved regenerative capacity in mice.
Biorevert herein suggests an alternative way of reverting cancer and aged cells to normal and young healthy cells without killing cells.
Why is reversion therapy yet to be applied in anti-cancer or -aging therapies?
It has been more than a century ever since the discovery of cancer and aged cells transformed into normal-like cells was reported. However, it has yet to be used as an anti-cancer and -aging therapies in patients because regulatory mechanisms underlying such biological phenomena are mostly elusive due to complex interactions within a network and no clue for systematic control of such reversion has been found till now.
To comprehend the nonlinear characteristics of molecular regulatory networks in cancer and aging, unraveling the mechanisms of such biological phenomena is necessary by applying various complex network control theories.
Reversion therapy vs. other therapies
Reversion therapy, with much fewer side effects, is NOT comparable to anti-cancer therapy or senolytics that kill cancer and aged cells. In addition, senomorphics inhibit SASP (senescence-associated secretory phenotype) of aged cells without considering the hallmarks of aging. In contrast, reversion therapy for aged cells can reduce the majority of the aging hallmarks as well as SASP. Finally, by following our mission to treat cancer as a chronic disease, we also consider reversion therapy to have a distinct objective in reducing the malignancy of cancer cells in comparison to differentiation therapy with its primary goal to differentiate cancer cells by decreasing stemness.
*RA(retinoic acids): A differentiation therapy for acute promyelocytic leukemia patients
- J. I. Joo, H.-J. Park, K.-H. Cho*, Normalizing Input–Output Relationships of Cancer Networks for Reversion Therapy. Adv Sci (2023).
- N. Kim, C. Y. Hwang, T. Kim, H. Kim, K.-H. Cho*, A cell fate reprogramming strategy reverses epithelial-to-mesenchymal transition of lung cancer cells while avoiding hybrid states. Cancer Res. 83, 956–970 (2023)
- S. R. Choi, C. Y. Hwang, J. Lee, K.-H. Cho*, Network Analysis Identifies Regulators of Basal-Like Breast Cancer Reprogramming and Endocrine Therapy Vulnerability. Cancer Res. 82, 320–333 (2022).
- S. An, S.-Y. Cho, J. Kang, S. Lee, H.-S. Kim, D.-J. Min, E. Son, K.-H. Cho*, Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts. Proc National Acad Sci. 117, 31535–31546 (2020).
- S. Lee, C. Lee, C. Y. Hwang, D. Kim, Y. Han, S. N. Hong, S.-H. Kim, K.-H. Cho*, Network Inference Analysis Identifies SETDB1 as a Key Regulator for Reverting Colorectal Cancer Cells into Differentiated Normal-Like Cells. Mol Cancer Res. 18, 118–129 (2020).
- K.-H. Cho*, S. Lee, D. Kim, D. Shin, J. I. Joo, S.-M. Park, Cancer reversion, a renewed challenge in systems biology. Curr Opin Syst Biology. 2, 48–57 (2017).
- K.-H. Cho*, J. I. Joo, D. Shin, D. Kim, S.-M. Park, The reverse control of irreversible biological processes. Wiley Interdiscip Rev Syst Biology Medicine. 8, 366–377 (2016).