Targeted Cancer Therapy, Narrowing our Focus

When it comes to cancer treatment techniques, the research community has narrowed its focus. The tried and true techniques of chemotherapy and radiation leads to global cell death of both healthy and cancer cells. While for many cancers, these therapies can be highly effective, there are many cancers for which this form of treatment falls short leading to relapse and death. Furthermore, there are some patients who cannot withstand these conventional forms of treatment, such as those greater than 60 years old. Cancer researchers are narrowing their focus by targeting the individual proteins within cancer cells specifically that are not behaving appropriately and are subsequently contributing to the progression of cancer. The goal is to develop anti-cancer therapeutics that disrupt the function of these rouge proteins, resulting in the prevention of further cancer progression. By designing therapeutics that specifically target the upset in the cancer cells, researchers hope to reduce toxicity often observed with standard chemotherapy and radiation levels and provide an alternative treatment option to those patients who cannot withstand conventional therapy techniques. This approach to cancer treatment is referred to as targeted therapy 1.

Proof of concept for the targeted therapy approach has been demonstrated by the development of Gleevec®2. Gleevec® is a drug used to target a specific form of blood cancer, chronic myeloid leukemia (CML). Patients with CML often contain a mutation in which a fusion of two proteins, BCR and Abl, has occurred, forming BCR-Abl. This fusion-protein is crucial to the continued progression of CML. Gleevec® specifically targets BCR-Abl, not the individual BCR or Abl proteins that persist in healthy cells, preventing continued cancer progression. Gleevec® was the first drug of its kind and has served as a promising example for the use of the targeted therapy approach in the treatment of cancers 2. However, it is not yet clear if this approach will work for other types of cancers that lack such an indicative characteristic.

Researchers are currently investigating the possibility of targeting the interaction of the tumor suppressor protein p53 with the human double minute 2 (HDM2) protein for the treatment of a variety of cancers 3,4. In a healthy cell, HDM2 interacts with p53 to mark p53 for disposal, thereby keeping the cellular level of p53 low 3–5. When a healthy cell is damaged however, HDM2 should no longer interact with p53, allowing p53 to signal to the cell to either fix the damage or undergo cell death, preventing cancer and disease 3–5. Unfortunately, in many forms of cancer the level of HDM2 present in the cell increases due to the mis-regulation of HDM2. This leads to the inappropriate, persistent interaction of p53 and HDM2, which prevents p53 from telling the cell to fix the damage or undergo cell death 3,4,6,7. Without the signal from p53, the cell continues to divide, resulting in cancer 3,4,6,7. Many cancers have been described to result from the increased levels of HDM2 and its persistent interaction with p53, including the fatal blood cancer acute myeloid leukemia (AML) 3,4,6,7. Treatment of AML by conventional chemotherapy and radiation methods has proven to not be sufficient to induce remission, so much so that patients under 60 years old diagnosed with AML that undergo the currently available chemotherapy treatment only have a 35-40% remission rate 6–8.

Many drugs have been developed to specifically disrupt the interaction of p53 with HDM2 with the hope to increase the odds of remission in AML patients 3,4,6,7. Disrupting their interaction in cancer would allow p53 to signal for cellular repair or for the cell to undergo cell death, allowing the body to assist in the effort to discontinue cancer progression. A specific drug of interest is the small molecule inhibitor MK-8242 which is currently under development by Merck & Co 6. The preclinical evaluation suggests that MK-8242 is a very potent small molecule inhibitor of the p53/HDM2 interaction which results in halting cell growth and leading to cell death 6.

Recently, MK-8242 was evaluated in numerous Phase I clinical trials to evaluate potency, toxicity, and attempt to establish the appropriate, tolerated dose in patients with AML (NCT01635296, NCT01773408, NCT02545283) 6. The results of the study performed by Ravandi et al. suggest that MK-8242 is reasonably safe when administered at a dose up to 300 mg two times a day for 7 days straight followed by 14 days of no drug, however these findings require significant further evaluation 6. The most severe side effects included gastrointestinal and hematological upsets. The study was successful in showing that treatment with MK-8242 lead to increased levels of p53 in some of their patients, however it was suggested that a stronger response would be obtained if MK-8242 was used in a combination therapy with Cytarabine 6. Cytarabine is a currently approved AML drug that interrupts DNA synthesis, therefore damaging the cell beyond repair and preventing further cell growth. Preclinical studies with HDM2 inhibitors have suggested that they can sensitize cancer cells to the effects of Cytarabine, potentially improving the effects of Cytarabine in the treatment of AML 6.

While MK-8242 is still in the early stages of drug development, it shows promising results for further development as a targeted therapeutic toward AML 6. Furthermore, MK-8242 has also been studied for use in Liposarcoma, the cancer of the connective tissues, suggesting that it may be useful for many different types of cancer in which levels of HDM2 are elevated 7. Targeted therapy is still earning its place in the world of cancer treatment methods, however, the success of Gleevec® and the ongoing studies of MK-8242 suggest that we are making progress. As researchers narrowing their focus from the global approaches of chemotherapy and radiation, they broaden the treatment methods available for many types of cancers, specifically cancers with poor responses to these standard, tried and true methods.

 

  1. The American Cancer Society Medical and Editorial Content Team. What Is Targeted Cancer Therapy? June 6. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/targeted-therapy/what-is.html. Published 2016. Accessed March 13, 2017.
  2. Wong S, Witte ON. The BCR-ABL story: bench to bedside and back. Annu Rev Immunol. 2004;22(1):247-306. doi:10.1146/annurev.immunol.22.012703.104753.
  3. Cheok CF, Verma CS, Baselga J, Lane DP. Translating p53 into the clinic. Nat Rev Clin Oncol. 2011;8(1):25-37. doi:10.1038/nrclinonc.2010.174.
  4. Brown CJ, Cheok CF, Verma CS, Lane DP. Reactivation of p53: from peptides to small molecules. Trends Pharmacol Sci. 2011;32(1):53-62. doi:10.1016/j.tips.2010.11.004.
  5. Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem. 2000;275(12):8945-8951. doi:10.1074/JBC.275.12.8945.
  6. Ravandi F, Gojo I, Patnaik MM, et al. A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Leuk Res. 2016;48:92-100. doi:10.1016/j.leukres.2016.07.004.
  7. Wagner AJ, Banerji U, Mahipal A, et al. Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors. J Clin Oncol. February 2017:JCO2016707117. doi:10.1200/JCO.2016.70.7117.
  8. Saultz J, Garzon R. Acute Myeloid Leukemia: A Concise Review. J Clin Med. 2016;5(3):33. doi:10.3390/jcm5030033.

 

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