Author and Reporter: Anamika Sarkar, Ph.D.
Today, the gold standard treatment for cancer is still chemo therapy or radiation therapy. Drugs are administered to treat patients with different doses, frequencies and combinations. It is recognized that the side effects of all these therapies lead to DNA damage responses (DDR) and their subsequent signaling alterations resulting in cellular functions. Moreover, it is well known that DDR is responsible for complex cross talks and feedback of signaling pathways for progrowth and apoptosis within intracellular as well as extracellular networks (in tissues).
Optimal combinations of drugs in respect of doses or frequencies or order of treatments of different drugs have been recognized as a powerful method of treatment of complex diseases. However, executing experiments of multiple possible combinations of drugs and cell lines can easily lead to very costly proposition. Lee et.al in their paper published in Cell (2012), titled “Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks”, reported from experimental results that when triple negative breast cancer (TNBC) cells are treated, with a combination of drugs – erlotinib, which is an EGFR inhibitor, at least 4 hours before of another drug, doxorubicin – the cells show higher apoptotic (cell death) responses. Other forms of treatments like, single administration of the drugs or treating the cells together with two drugs at same time, did not show any increased levels of apoptosis in TNBC cells.
They complemented their understanding of reason behind such unique behavior of TNBC cells, when exposed to time -stagger treatment of drugs, with systems level modeling. They used quantitative analysis of high throughput reverse-phase protein microarrays and quantitative western blotting of experiments. They chose to measure activation states of 35 signaling proteins at 12 time points following exposure to ertolinib and doxorubicin individually and in combinations. The authors used PLS (Partial Least Square) and PCA (Principle Component Analysis) methods for predictive analysis from data driven model.
They report from their systems level analysis that time – stagger treatment of TNBC with two drugs ertolinib and doxorubicin activate Caspase 8, a key apoptotic signaling component, which remains absent in other combinations of treatments of drugs. They hypothesized that early treatment of ertolinib, inhibits EGFR responses, which increases levels of activated Caspase 8 and gets amplified after getting exposed to the second drug doxorubicin.
Combination therapy in treating complicated diseases like cancer has many importance in making the dose and treatment efficient. However, due to complex nature of signaling pathways, it poses increasing amount of challenges. Lee et. al., address some of those challenges by bringing in synergistic collaborations among different fields – experiments and mathematical modeling, which is the future of drug development.
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GREAT POST, I connected it to all my LinkedIn Groups to spread out the visibility propensity of your post.
Thank you Aviva. Combination drug therapy is so important in today’s medicine, but very few address the time, order for optimal efficacy. This paper did address this important issue
They chose to measure activation states of 35 signaling proteins at 12 time points following exposure to ertolinib and doxorubicin individually and in combinations. The authors used PLS (Partial Least Square) and PCA (Principle Component Analysis) methods for predictive analysis from data driven model.
This is really where the laboratory technology, the experimental design, and the apllied statistics make a huge powerful reinforcing move forward. The 12 time points would also get into Prof. C Tsokos work with “stochastic differential equations”.
Dear Anamika,
Regarding your comment above, “Combination drug therapy is so important in today’s medicine”
I am starting to post my our research on Combination drug therapy for augmentation of circulating Endothelial Progenitor Cells in Cardiovascular disease.
Lev-Ari, A. & Abourjaily, P. (2006a) “An Investigation of the Potential of circulating Endothelial Progenitor Cells (cEPC) as a Therapeutic Target for Pharmacologic Therapy Design for Cardiovascular Risk Reduction.
“Part I: Macrovascular Disease – Therapeutic Potential of cEPCs – Reduction methods for CV risk.
Part II: (2006b) Therapeutic Strategy for cEPCs Endogenous Augmentation: A Concept-based Treatment Protocol for a Combined Three Drug Regimen.
Part III: (2006c) Biomarker for Therapeutic Targets of Cardiovascular Risk Reduction by cEPCs Endogenous Augmentation USING NEW COMBINATION DRUG THERAPY OF THREE DRUG CLASSES AND SEVERAL DRUG INDICATIONS. Northeastern University, Boston, MA 02115
Since One of the three drugs was recalled in 2007 — I could not submit this work to pub in a Journal.
Now, me and Dr. Larry will substitute this one drug with another, I’ll propose to him three for him to choose one and we will go ahead and submit the work.
Sounds great Aviva.
Anamika
Thank you Dr. Larry for bringing up importance of understanding stochastic behavior inside cell.
Also, I think dynamic nature of signaling pathway can give more insight into other signaling components, which can either inhibit or amplify the signal. Such an understanding can find new or modification of drug targets. Moreover, a systems level understanding as a tissue model can also give interesting insights, which can be translated into drug administration as local vs global.
Dr. Larry,
Per your comment above, I expect you to complement me for working thus hard to recruit Dr. Anamika to our Team to cover Computational Biology, Systems and Bioinformatics from a dynamic perspective.
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette