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Disclaimer:  This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on literature review at the time of the blog and may change as new evidence evolves.

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Cancer's Kryptonite: Innovative Cancer Therapies Unveiled by Science

Updated: 5 days ago


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How to Kill Cancer Cells

Cancer remains one of the most challenging diseases to treat, but researchers are continually developing new and innovative ways to combat it. Even so, the success rate remains underwhelming. This blog post explores promising new approaches like synthetic lethality and metabolic targeting.


Standard of Care Cancer Therapies

While traditional methods like chemotherapy, surgery, and radiation remain the standard of care in the treatment of cancer, newer methods such as synthetic lethality and metabolic targeting are showing great promise in research and clinical settings. Here are some of the key strategies currently being explored:


  • Targeting DNA and Tubulin: Chemotherapy and Tumor-Treating Fields (TTF) use a two-pronged attack: damaging DNA and disrupting tubulin, a protein vital for cancer division. This prevents cancer cells from properly dividing and repairing their genetic material, often enhancing treatment efficacy when combined with microtubule-targeting agents [1].

  • Oncogene Targeting: Some cancers rely on oncogenes—mutated genes that drive their characteristic uncontrolled growth. Targeting therapies such as hormonal treatments, monoclonal antibodies, and tyrosine kinase inhibitors work by blocking these oncogene-driven proteins, thus slowing tumor progression [2].

  • Immunotherapy: Therapies like checkpoint inhibitors (PD-L1, CTLA-4, LAG3), oncoviral therapy, cancer vaccines, and CAR T-cell therapy enhance the immune system’s ability to detect and destroy cancer cells. While promising, immunotherapy’s success varies across patients, and side effects must be managed carefully [3].


Emerging Cancer Therapies

Master Regulator Targeting: Cancer cells often rely on specific transcription factors that control multiple genes involved in growth and survival. Targeting these “master regulators” can disrupt entire cancer-driving pathways, making them valuable therapeutic targets [4].

  • Metabolomic Targeting: Cancer cells have unique metabolic demands that can be exploited for treatment. In general, metabolic oncology aims to deprive cancer cells of energy, rendering them vulnerable to being killed more easily by additional therapies. Strategies such as glutamine dehydrogenase inhibitors, amino acid deprivation (e.g., L-asparaginase), metabolomic drugs like metformin, and dietary interventions like ketogenic diet aim to cut off critical fuels for energy and metabolic growth pathways that cancer cells rely on [5].

  • Synthetic Lethality (SL): By exploiting genetic vulnerabilities unique to cancer cells, synthetic lethality therapies use drugs like PARP inhibitors to selectively kill tumors without harming normal cells. This approach targets genes cancer cells depend on for survival, effectively trapping them in a lethal state when combined with existing mutations [6]. Many simple repurposed drugs and supplements may also work as SL pairs, offering underutilized low-toxicity therapies.

 

Synthetic Lethality: A Promising Frontier

This is not the first time synthetic lethality has been discussed in these blogs. You might remember it being mentioned in a previous blog entitled “Unlocking the Anticancer Potential of Statins: A Revolutionary Study.” That was a great introduction to synthetic lethality, but let's go more in-depth. As the definition says above, SL exploits the genetic vulnerabilities specific to cancer cells. What does this mean? 


A more straightforward explanation is that SL arises when two genetic alterations result in cell death, whereas each alteration alone is non-lethal [7]. Cancer cells often have mutations that disable specific genes. The cell then compensates by relying on a different gene. The reliance on compensatory genes makes them uniquely vulnerable to therapies targeting the SL gene partner [7].


One of the most well-known applications of synthetic lethality is the use of PARP inhibitors in BRCA-mutated breast and ovarian cancers. BRCA is a gene involved in DNA repair; a mutation in a BRCA gene renders the cell less able to repair DNA mutations. The cell, then, is forced to rely on a different gene, the PARP gene, to repair DNA breaks. PARP inhibitors exploit this synthetically lethal relationship by preventing cancer cells from repairing DNA damage, leading to catastrophic DNA damage and selective death while sparing normal cells [7]. Another example is KRAS-mutant colorectal cancer, particularly sensitive to the inhibition of PLK1, the anaphase-promoting complex, further highlighting how targeting specific genetic dependencies can disrupt tumor growth [8].

 

Historically, predicting SL interactions has been challenging due to the complexity of molecular networks in human cells and the limitations of model organisms [8]. However, advancements in CRISPR screening have led to an explosion in the identification of SL relationships in cancer cells [9]. 


What’s Currently Brewing in SL Therapies?

While pharmaceutical companies actively identify promising SL relationships to develop novel, patented oncology drugs, there is no reason to wait. The significant uptick in SL databases presents a unique opportunity to couple SL to drug repurposing – massively broadening the scope of potential treatments. For example, there is a well-established SL relationship between the co-inhibition of the estrogen receptor and a metabolic gene called PIK3CA in estrogen receptor-positive breast cancer [10]. Knowing this, drug databases were searched to identify inhibitors of PIK3CA. Surprisingly, caffeine is an excellent inhibitor of PIK3CA [11]. The next step was to search for clinical validation of this SL relationship. To great surprise (again), a study published in 2015 unknowingly provided validation [11]. The study aimed to assess coffee consumption's influence on patient and tumor characteristics and disease-free survival in Sweden's population-based cohort of 1,090 patients with invasive primary breast cancer [11]. After stratification according to ER status, the study showed that increasing coffee consumption remained significantly associated with smaller invasive tumor sizes among women with ER+ tumors. In contrast, no significant association was found among ER− tumors [11].


Additionally, the study followed 1,082 patients for up to 9 years to assess the impact of coffee consumption on breast cancer prognosis [11]. Disease-free survival significantly improved among tamoxifen-treated women with ER+ tumors drinking two or more cups of coffee daily [11]. Among these women, there was a 49% decreased hazard of early breast cancer recurrence when drinking moderate to high amounts of coffee compared with low coffee consumption [11]. Even though the authors of this study proposed a different mechanism of action for this striking observation, the organization Astron.Health suggests that the observed benefit may be due to the synthetically lethal relationship between ER+ inhibition with tamoxifen and the ability of caffeine to inhibit PIK3CA, thus inducing SL in this patient subgroup. 

Medical News Today - coffee and breast cancer
Whiteman, H. (2015, April 23). [14]

This example is one of many that demonstrates the coupling of SL databases to drug repurposing that identifies unique and unexpected therapeutic opportunities. Astron.Health has a growing database of repurposed drugs and natural products that can be used to target the specific synthetic lethal relationships unique to each patient. This can tremendously benefit patients because it is an evidence-based way to narrow down the hundreds of repurposable drugs and supplements with various degrees of anticancer data to a personalized protocol that may be the most optimal.

 

For example, both metformin and aspirin have many anticancer data from cell studies in the laboratory to population-level data. However, metformin may benefit people with the upregulation of a MYC gene due to its ability to inhibit MYC’s synthetically lethal gene partner, PRKAB1. Additionally, aspirin may be of specific benefit to patients harboring the amplification of an oncogene called CCND1 due to its ability to inhibit it directly. In summary, the power of coupling drug repurposing to the emerging databases on synthetic lethal relationships in cancer represents a powerful new tool in personalized cancer therapy.


Metabolic Targeting: Exploiting Cancer’s Achilles' Heel

Cancer cells often exhibit an altered metabolism compared to normal cells, a phenomenon known as metabolic reprogramming [12]. This different metabolic profile presents an opportunity for targeting therapies.

Metabolic targeting strategies include:


  1. Glutamate inhibitors inhibit key metabolic enzymes such as glutamine dehydrogenase and glycolysis regulators [12]. While glutamine inhibitors remain an active research focus, these drugs remain in the clinic, where we closely monitor their progress.

  2. Drugs and supplements that pressure normal glycolysis in cells and thus significantly impact enhanced sugar-burning metabolism of cancer cells add to the stressors to improve the outcomes of standard-of-care therapies. 

  3. Exploiting metabolic vulnerabilities through diet modification, including the ketogenic diet and cholesterol depletion [12], lends itself well to drug repurposing. Safe and established drugs like metformin and lipophilic statins deprive cancer cells of critical fuels and signaling molecules. 


Otto Warburg’s discovery of aerobic glycolysis, the “Warburg effect,” opened the door to understanding how cancer cells rewire metabolism for survival [13]. Since then, research has revealed additional vulnerabilities, such as oxidative stress dependence and altered nutrient processing, presenting new opportunities for therapeutic intervention [13]. These metabolic therapies focus on three key areas: tumor cell metabolism, the tumor microenvironment, and whole-body metabolism [13]. Researchers are developing promising treatments beyond traditional chemotherapy and radiation by disrupting pathways like glucose transport, nucleotide and amino acid metabolism, fatty acid synthesis, and mitochondrial function. 

I know that was a lot of information, but combining these two approaches could be the new “dream team” for precision cancer therapy.


The Future of Cancer Treatment

While SL and metabolic targeting show great promise, they are not yet fully integrated into standard cancer care. However, innovative companies are working to change this.

Organizations such as MeakinMetabolicCare.com and Astron Health are at the forefront of developing and implementing these cutting-edge approaches. These companies aim to offer more personalized and effective cancer therapies by translating the latest research into practical treatment.  


As research advances, we can expect to see more targeted, effective, and personalized cancer treatments emerging. SL and metabolic targeting are increasingly important in the fight against cancer. 


Stay strong and curious, and be your own best doctor,

Chuck Meakin MD


Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.


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Citations

  1. M.S. Poruchynsky, E. Komlodi-Pasztor, S. Trostel, J. Wilkerson, M. Regairaz, Y. Pommier, X. Zhang, T. Kumar Maity, R. Robey, M. Burotto, D. Sackett, U. Guha, & A.T. Fojo, Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins, Proc. Natl. Acad. Sci. U.S.A. 112 (5) 1571-1576, https://doi.org/10.1073/pnas.1416418112 (2015)

  2. Oncogenes. Cleveland Clinic. (2024, December 19). https://my.clevelandclinic.org/health/body/24949-oncogenes

  3. What is immunotherapy?. Cancer Research Institute. (2023, October 6). https://www.cancerresearch.org/what-is-immunotherapy

  4. Chan, S. S., & Kyba, M. (2013). What is a Master Regulator?. Journal of stem cell research & therapy, 3, 114. https://doi.org/10.4172/2157-7633.1000e114

  5. Suri, G. S., Kaur, G., Carbone, G. M., & Shinde, D. (2023). Metabolomics in oncology. Cancer reports (Hoboken, N.J.), 6(3), e1795. https://doi.org/10.1002/cnr2.1795

  6. Du, Y., Luo, L., Xu, X., Yang, X., Yang, X., Xiong, S., Yu, J., Liang, T., & Guo, L. (2023). Unleashing the Power of Synthetic Lethality: Augmenting Treatment Efficacy through Synergistic Integration with Chemotherapy Drugs. Pharmaceutics, 15(10), 2433. https://doi.org/10.3390/pharmaceutics15102433

  7. Zhang, B., Tang, C., Yao, Y. et al. The tumor therapy landscape of synthetic lethality. Nat Commun 12, 1275 (2021). https://doi.org/10.1038/s41467-021-21544-2 

  8. Kaelin W. G., Jr (2009). Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome medicine, 1(10), 99. https://doi.org/10.1186/gm99

  9. Previtali, V., Bagnolini, G., Ciamarone, A., Ferrandi, G., Rinaldi, F., Myers, S. H., Roberti, M., & Cavalli, A. (2024, July 2). New horizons of synthetic lethality in cancer. Journal of Medical Chemistry. https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00113 

  10. Crowder, R. J., Phommaly, C., Tao, Y., Hoog, J., Luo, J., Perou, C. M., Parker, J. S., Miller, M. A., Huntsman, D. G., Lin, L., Snider, J., Davies, S. R., Olson, J. A., Jr, Watson, M. A., Saporita, A., Weber, J. D., & Ellis, M. J. (2009). PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer research, 69(9), 3955–3962. https://doi.org/10.1158/0008-5472.CAN-08-4450

  11. Simonsson, M., Söderlind, V., Henningson, M., Hjertberg, M., Rose, C., Ingvar, C., & Jernström, H. (2013). Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status. Cancer causes & control : CCC, 24(5), 929–940. https://doi.org/10.1007/s10552-013-0169-1

  12. Apaolaza I, San José-Enériz E, Valcarcel LV, Agirre X, Prosper F, Planes FJ (2022) A network-based approach to integrate nutrient microenvironment in the prediction of synthetic lethality in cancer metabolism. PLoS Comput Biol 18(3): e1009395. https://doi.org/10.1371/journal.pcbi.1009395

  13. Xiao, Y., Yu, T.-J., Xu, Y., Ding, R., Wang, Y.-P., Jiang, Y.-Z., & Shao, Z.-M. (2023, August 8). Emerging therapies in cancer metabolism. ScienceDirect. https://www.sciencedirect.com/science/article/pii/S1550413123002656 

  14. Whiteman, H. (2015, April 23). Coffee “could halve breast cancer recurrence” in tamoxifen-treated patients. Medical News Today. https://www.medicalnewstoday.com/articles/292879


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