Precision medicine is an evolving therapeutic approach in health care industry, particularly for cancer care. Recently, this approach is also being considered for neurodegenerative diseases and other rare diseases. Though, focus of this article is Precision medicine – Oncology.
What is Precision Medicine?
Precision Medicine, also known as Personalized medicine, is a systematic approach of treating a disease based on patients’ genomic profile which enables physician to prescribe effective drug combination for a particular patient and also helps physician to adopt the best treatment regimen. You can find a simplified explanation of personalized medicine for cancer care here.
Why Precision Medicine?
In contrast to some of the disease setting where ‘one drug fits all’ approach works, for example, metformin would work mostly for diabetic patients. However, the same approach does not work for patient who requires an organ transplantation. Supposing, if a physician has to choose an organ donor, he/she cannot select a donor randomly rather blood, HLA compatibility tests need to be done in order to understand patients’ requirements and prevent complications that arises due to host-graft rejection. Precisely, the aim of precision medicine approach is to study the disease setting in a particular patient and propose therapy that works best for the patient. Such an approach is indeed necessary to treat disease like cancer as it can ensure good success rate, and most importantly ensures cost reduction due to repetitive therapy cycles and redundant administration of multiple drugs.
Why Precision Medicine for Cancer?
Cancer is multi-dimensional as it spreads in all possible direction, where host cells are transformed and immunity is hijacked by tumour cells. Transformation of host cells is due to accumulation of multiple mutations which survives immune attack. Such a transformation process may be exclusive in every cancer patient because of the pattern of genomic aberration acquired originally or even eventually to escape from host immunity that makes every patient unique. Therefore, ‘one drug fits all’ does not work in this disease setting rather ‘drug to suit an individual’ should be the strategy employed in treatment of cancer and precision medicine promises to offer customized therapy.
Image source: National Cancer Institute
Fundamentals of Precision Medicine
Pharmacogenomics is a fundamental aspect of Precision Medicine. It is a branch of pharmacology which deals with understanding the drug action under a given set of gene aberrations, therefore enables one to predict the patients’ response to a particular drug. For example, consider a patient with BRAF mutation. In this genome setting, there is constitutive activation of MAPK pathway (RAF -> MEK -> MAPK/ERK), which equips the tumour cell with sophisticated cell survival mechanisms. Under such conditions, one can select Trametinib that inhibits MEK and thereby inhibits MAPK pathway [Trametinib is an FDA approved drug for metastatic melanoma harbouring BRAFV600E mutation]. Another example to substantiate the importance of pharmacogenomics is: drug action w.r.t to different types of gene aberration pertaining to a single gene. Pemigatinib is a FGFR1/2/3 inhibitor which is generally effective in patients with FGFR2–CLIP1 fusion, but exhibits resistance in case of FGFR2 N549H mutation condition (Krook MA et al., 2019). Therefore, the gene condition under which the drug works become an important criterion before prescribing a drug.
However, does that mean ‘One gene, one drug’ approach, an accurate way to predict the right drug combinations?
Beyond one gene, one drug approach
As discussed earlier, cancer progresses due to accumulation of multiple mutations, some could be important drivers whereas others could just be passengers. Driver mutations are gene aberrations that are important in driving cancer whereas passengers may or may not be contributing to the tumour progression. Therefore, when we analyse patient profiles, it is important to examine the complete set of gene aberration to get a holistic perspective. Hypothetically, if a patient has KRAS (GOF) mutation and TSC2 (LOF) mutation, one should not prescribe drug targeting KRAS mutation alone. Since, targeting only KRAS mutation pushes tumour cell to leverage on another important cell survival mechanism i.e., MTOR pathway. MTOR pathway is also upregulated due to the loss of TSC2 gene, hence a drug combination that targets KRAS and MTOR pathway could be a better strategy to employ in this case.
Although, precision medicine strategy has evolved ever since its introduction into healthcare industry, yet there are considerable efforts going on to understand its loopholes and bridge the gap by considering multiple factors such as immune profile and gut microbiome profile of cancer patients. In my next article, I will be emphasizing on the advancements in precision medicine as a follow up of this article.
Krook MA, Bonneville R, Chen HZ, Reeser JW, Wing MR, Martin DM, Smith AM, Dao T, Samorodnitsky E, Paruchuri A, Miya J, Baker KR, Yu L, Timmers C, Dittmar K, Freud AG, Allenby P, Roychowdhury S.Cold Spring Harb Mol Case Stud. 2019 Aug 1;5(4): a004002.
GOF: Gain of function
LOF: Loss of function
MAPK: Mitogen activated protein kinase