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Targeted therapy vs Chemo therapy

August 28, 2017

 

First, a figure shows why targeted therapy is, in certain circumstance, slightly better than chemo. Of course still less competitive than immunotherapy which will be discussed in the another topic.

 

In terms of toxicity:

Chemo targets all the fast growing cells and therefore bring non-minor damages  to normal cells. Some of the side effects are:

  • Immunosuppression and myelosuppression: paralyzing the bone marrow and leading to a decrease of white blood cells, red blood cells, and platelets. Consequently, causes anemia and further causes fatigue. In very severe myelosuppression, almost all the bone marrow stem cells are destroyed.

  • Gastrointestinal damage: Nausea, vomiting, anorexia, diarrhea, abdominal cramps, and constipation are common side-effects of chemotherapeutic medications that kill fast-dividing cells

  • Hair loss (Alopecia):Caused by chemotherapy that kills rapidly dividing cells

  • Secondary neoplasm: The most common secondary neoplasm is secondary acute myeloid leukemia.

  • Cardiotoxicity: The cause of this is most likely due to the production of free radicals in the cell and subsequent DNA damage.

  • Nephrotoxicity: an be caused by tumor lysis syndrome and also due direct effects of drug clearance by the kidneys

 

One the other hand, targeted therapy only targets specific tumor alternations making normal cell exempt from being damaged.

 

 

In terms of relapse:

Due to the tumor heterogeneity and targeted therapy'specificity on target mutation, this therapeutic strategy allows tumor (especially highly heterogeneous tumor) to have better change to develop resistance through secondary mutations. 

  • Secondary mutations that disrupt / neutralize drug binding(EGFR T790M)

  • Up-regulation of second kinase

  • Activation of alternative pathway(EGFR->MET)

 

 

Once even one small subclone acquires key secondary mutations that give it ability to escape current inhibitory state. It may become dominant and end up with relapse.

 

 

On the other hand, it is not that easy for tumor to get relapse thanks for oncogene addiction: mutations are disadvantageous without the existence of another mutation (most likely driver mutation) it addicted to. Targeted therapy usually targets mutations that render tumor survival advantage. without this advantage the tumor may rapidly die before acquiring secondary mutation. This is the fundamental of targeted therapy

 

 

How can we minimize the chance of relapse?

  • Combinatorial medicine instead of sequential medicine.

  • Synthetic lethality. Combination of deficiency leads to cell death. For example using RAPP1 inhibitor in context of BRCA 1/2 mutation. RAPP1 and BRCA repair single and double strand DNA break respectively. The inhibition of RAPP1 can cause double strand DNA break and lead to cell death without BRCA 1/2 repairing them.  

  • Target truncal mutations which dominate the tumor. The challenge is how to estimate the overall frequency of targeted mutation in entire tumor focus.

 

 

 

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