I was going through a couple of studies where the spectrum of cancer cells within a single biopsy site were shown to be heterogeneous having different expression of genes and showing non-Darwinian evolution. What are the options of treating patients using personalized medicine if we have to take into account each and every single cancer cell throughout the body which, downs the argument in favor of personalized therapy.
http://pipeline.corante.com/archives/2012/03/20/personalized_medicine_for_cancer_try_every_cell.php
Heterogeneity is a problem with personalized therapy, which might be overcome if there are driver mutations present in all cells. However, the whole concept of personalized therapy is for mass media and bureaucrats, rather than for patients. The greatest problem of this type of approach is specificity, because it is very difficult to find a signaling pathway completely specific for cancer cells and a drug completely specific for this signaling pathway. Then, if you want to be efficient, you will need to associate several "specific" drugs, with unpredictable side effects. Then, due to the limited size of the subgroups, it will be impossible to do clinical trials.
In contrast, it may be more useful to think in terms of a universal behavior of cancer cells and of protection of normal cells, which can be easily predicted. For instance:
https://www.researchgate.net/publication/258041602_Toward_a_universal_treatment_for_cancer_cell_inflation_assisted_chemotherapy?ev=prf_pub
Article Toward a universal treatment for cancer: Cell inflation assi...
The trick is going to be first to identify upregulated cell surface epitopes in a biopsy, then targeting drug carriers to these epitopes and have multiple drugs delivered that affect different stages of the cell cycle and also potentiate each others activity.
I do not think there exists a magic bullet and it will not exist in personalized therapy as well. However, personalized therapy definitely makes a strong case in terms of combination therapy wherein we can atleast alleviate some of the side effects from standard chemotherapy. Caution and monitoring is absolutely essential since targeting any pathway will have effects on other pathways that have crosstalk and the effect of a particular targeted therapy may be different for each patient.
Hi Vidya: It appears that personalised Cancer Therapy perhaps would be the best at this point of time as each individual's cancer is different from another even though it might be placed in the same broad category of Carcinoma or sarcoma etc. After carefully judging each patient's cancer type, nature, immunological status etc., only individualised therapeutic regimen needs to be devised to obtain best kind of results, I suppose
Personalization of cancer therapy could be done, by beginning with a detailed examination. The use of substances that can inhibit cancer cell growth and development and does not damage normal tissue cell is very favorable compared to chemotherapy, which generally will damage the cells surrounding the cancer cell
I think a very useful tool could be a taxonomy or classification for a systematic treatment of cancers. Thereby, I doesn't mean a classification for breast cancer, prostata cancer,.... mandatory. But especially for treatment markers.
Also the question raises, whether it is possible to push the differentiated cancer status in a defined one.
The heterogeneity you speak of is exactly why we need personalized therapy. If you deem a tumor to be too heterogeneous for personalized therapy to work, what makes you think that standard therapy will work? As Martyn Sharpe pointed out, if we find elevated levels of surface molecules (like HER2 in breast cancer) that differentiate tumors from normal tissues we can use specific, personalized blends of different carriers for each tumor.
Felix; Yours is nothing but " ifs and buts". There are various missing points in our understanding about what cancer is all about. Of course can cells are always heterogeneous. Some surface molecules do appear on cancer cells, but how do you know they are there all the time and in 100% of cells? That is where the fallacy comes
Prasanta, I respectfully agree that we need to know more. I simply put forth that if ,as Abbas suggested, cancer is too heteregeneous for personalized therapy then standard therapy is already inadequate. If we can agree that standard therapy is inadequate due to this heterogeneity then a more personalized therapy is the only logical approach.
Dear Abbas:
The heterogeneity of genetic alteration is indeed the main limitation of targeted therapy in solid tumors. Very commonly, tumors with defined driver mutations (as ALK-positive Lung Cancer or GISTs) not only have many different other mutation in the same tumor simultaneously, but acquired mutations appear after a targeted therapy is used for months or years, causing tumor progression. Small Cell lung cancer itself can have more than 30 oncogenic mutations at diagnosis on a single tumor sample.
The problem itself starts on the definition of "What is a driver mutation?". KRAS and TP53 mutations in many tumors can enhance resistance pathways, but their inhibition doesn't really stop tumor progression clinically (at least not until now in solid tumors). On the other hand, in diseases as Chronic Myelogenous Leukemia, although there are cases of clonal evolution, the inhibition of the BCR/ABL positive cells with kinase inhibitors is extremely effective, and heterogeneity is not really an issue. However, in solid tumors as ALK-positive lung cancer, the development of overexpression of EGFR or Gatekeeper mutations (L1196M) cause resistance to crizotinib and progression of disease within months. Therefore, Personalized therapy is not only 'personalized' in an Individual, but is also a dynamic phenomenon that changes over time and re-biopsies are now becoming standard to achieve an effective persistent target inhibition. Combination therapy might potentiate the efficacy of the therapies, but toxicity limits this approach importantly.
C.A Perez, MD
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