Predictive, Preventive and Personalized Medicine & Molecular Diagnostics

Biography

Biography: Dhavendra Kumar

Abstract

Cancer is a genetic disease at the cellular level leading to successive organ/ system structural and functional dysfunction. This fundamental concept has led to the ‘gene-molecule’ family basis of carcinogenesis leading to development of the ‘targeted molecular therapy’ and ‘stratified medicine’ approaches in clinical oncology. Designing and developing the new therapeutic approaches in clinical oncology require understanding of the complex molecular pathways involved in common cancers. This is often facilitated by the outcome of molecular genetic analyses in rare Mendelian cancer family syndromes. Investigations in dominantly inherited cancer predisposing disorders, for example tuberous sclerosis (TSC) and neurofibromatosis type 1 (NF1), have led to the identification of activated mTOR molecules as one of the major steps in carcinogenesis. Clinical trials using the potential mTOR inhibitors, for example Rapamycin & Sirolimus, have shown promising results in substantially limiting development and progression of TSC tumors (pulmonary lymphangiomas and renal cell cancers). The scope of mTOR inhibitors is extended to NF1 and other cancer predisposing syndromes sharing the mTOR molecular pathway. Several protein kinase inhibitors targeting epidermal growth factor receptors (EGFRs) are now licensed for treating various cancers. NICE recommends transtuzumab (Herceptin) with or without paclitaxel or docetaxel in HER2 positive early breast cancer and with cisplatin for metastatic gastric cancer. K-RAS mutation testing is recommended in sporadic and inherited colorectal cancer (CRC). Mutations in K-RAS are shown to have negative predictive power in CRC patients treated with Cetuximab and panitumumab, EGFR binding monoclonal antibodies, in combination with irinotecan for improved response rates. If the K-RAS mutation was present, the patient should not be offered cetuximab, avoiding additional toxicity and expense of cetuximab, Thus CRC patients with wild K-RAS gene might benefit from cetuximab or panitumumab. The non–small cell lung cancer (NSCLC) is the most common type of lung cancer with specific cellular characteristics and genetic constitution. Up to 7 percent of NSCLC have an abnormal version of the anaplastic lymphoma kinase (ALK) gene, most common among non-smokers and contribute to the growth of cancer cells. The most common drug for treating lung cancer, crizotinib (Xalkori) targets the protein produced by the abnormal ALK gene. Studies provide evidence for ALK-positive NSCLC show significant tumor shrinkage. FDA has now approved ALK gene test as a requirement for prescribing Xalkori in NSCLC. Patients with malignant melanoma, another common cancer among Caucasians, are likely to benefit from targeted approach using the mutation testing in the BRAF and c-kit-activating genes. The multiple kinase inhibitor, Sorafenib does not work in BRAF-mutated melanoma compared to good response of the second-generation PLX4720. Drugs that target BRAF may also be important in treating other tumours in which BRAF mutations are common including thyroid cancer (45%), ovarian cancer (10 %) and colorectal cancers (13 %). The practice of molecular stratification and targeted specific cancer pharmacotherapy has generated wide interest and rapid acceptance. This approach supports the concept of personalized therapy and is the basis of Stratified Medicine, a major revolution of clinical medicine in the genome era.