Reversing Cancer Cells to Normal: Korean Researchers Launch Digital Twin Therapy

Despite the revolutionary nature of the discovery, there are multiple challenges to address prior to moving towards cancer reversion in patients:

Complexity of Human Tumors: Lab models are controlled environments. Actual tumors exist with their own microenvironments which can force abnormal interactions by utilizing immune cells, nutrient supply, and other extracellular cues that could impact reversion.

Chemical Delivery: Specifically and safely inhibiting multiple master regulators in human patients is not trivial. Any number of approaches, including small molecules, RNA-based drugs, or CRISPR-delivered knockdowns need to be improved to be precise.

Stability: Reverted cells may not remain reverted. If residual mutations or contingencies within the environment push reverted cells back into another attractor of malignancy, it is possible they relapse back into malignancy.

Cancer-specificity: The regulators that were discovered (MYB, HDAC2, FOXA2) were discovered using CRC lineage cells. Each one of the cancers will need to have its own respective identification of reversion regulators.

Safety: Forcing cells into differentiation must be carefully characterized to avoid generating dysfunctional cell types or any unanticipated side effects. Long-term studies will be needed.

Roadmap Towards Clinical Translation

In order for this technology to move from the lab to the clinic, specific stages will need to be accomplished:

Expand to Other Cancers: Using the same computational-experimental pipeline, investigators will need to find reversion regulators for breast, lung, and pancreatic as additional examples.

Safe Developed Drugs: Be it small-molecule inhibitors, RNA drugs, or protein degraders, drugs need to be developed that are specific to the master regulators to target them safely. 

Patient Stratification: It is likely that not all tumors will be similarly reprogrammable. Single-cell analysis may inform which patients are best suited by establishing whether their tumors were likely to contain a transitional state to be reversed. 

Preclinical Safety Testing: Monitoring the quality of reverted unicellular models or systems must be conducted with long-term length of time and during properly controlled experiments with animal models to ensure that reverted states are retained safely. 

Initial supervised trial in the clinic: An appropriate size and stratified patient sample will help the initial clinical trial to ensure feasibility of study parameters, using molecular biomarkers to affirm that reversed states have occurred within the patients.

Wider Scientific and Ethical Issues

This study represents more than a technical accomplishment — it represents a new paradigm regarding cancer in the scientific community. It proposes a shift away from war to eradicate malignant cells to some form of rehabilitation strategy. However, ethical and social issues are essential:

Access and Equity: new therapies are potentially going to create more inequities, especially if the treatments are expensive, or will only exist in elite care centers.

Regulation: clinical endpoints will have to change from tumor shrinkage and survival, to perhaps assessing “normalized” cells that continue to exist but that do not proliferate: these “cured” cells may be present even though not lethal. 

Long-term Surveillance: reversion therapy may need continued molecular surveillance for life to determine whether reverted cells continue to be stable.

The Bottom Line 

KAIST’s team’s discovery is ambitious and hopeful. They demonstrate how reversion therapy can beat the back of state-of-the-art methods including single-cell genomics, Boolean-network modeling, and experimental validation that some circuits of cancer cells can be subverted toward a normal state. The discovery provides proof-of-principle for cancer reversion (a therapeutic paradigm that does not focus on killing cancer, but rather reprogramming it back to health).

Nevertheless, challenges remain, but this research revealed a glimpse of a future where cancer research in the clinic can become a practice free from — or with limited complexity associated with — killings, but more focused on restoring health. If successful, reversion therapy could become a legitimate treatment modality on par with immunotherapy and precision medicine in the strides made against cancer. 

We are just as hopeful that the spirit of innovation and boundary-pushing discoveries will be invigorated for the community in this place here at Atlantic International University (AIU). AIU students on alternative ways to think, push tradition, and create solutions that shift change. If you are ready to partner with a worldwide and democratic network of transformations that will change the course of humanity and knowledge, only join AIU.