As we learned in class, cancer has evolved to manipulate the cell cycle and all of its components to ensure its survival. Despite the cell cycle containing multiple corrective methods to prevent the occurrence of tumors, cancer cells have a way of avoiding the detection of normal tumor suppressors and encouraging activation of proto-oncogenes, among other hallmarks. Due to the aggressive nature of cancer cells, it has been difficult to provide cancer patients with effective treatment that would not cause adverse reactions. It has also been a challenge to treat all cancer patients indiscriminately as each cancer type is affected by various locations within a normal pathway and certain cancers have an affinity to certain cell types. The discussion for an ultimate cure of more than one type cancer has become a possibility. A recent article published in Nature Medicine describes the development of the first Hedgehog inhibitor cancer drug.According to the
article, a phase II trial led by Ervin Epstein found that participants with Basal Cell Carcinoma Nevus Syndrome (BCCNS) taking vismodegib developed only 4 new tumors on average within a year compared to 24 new tumors in the control group. Coincidentally participants in the vismodegib group witnessed a reduction in size of existing skin lesions while those in the control group witnessed growth in size. This drug was not only proven effective in BCCNS patients, but also in patients affected with pancreatic cancer, medulloblastoma, and “17 other types of cancer”.
article, a phase II trial led by Ervin Epstein found that participants with Basal Cell Carcinoma Nevus Syndrome (BCCNS) taking vismodegib developed only 4 new tumors on average within a year compared to 24 new tumors in the control group. Coincidentally participants in the vismodegib group witnessed a reduction in size of existing skin lesions while those in the control group witnessed growth in size. This drug was not only proven effective in BCCNS patients, but also in patients affected with pancreatic cancer, medulloblastoma, and “17 other types of cancer”.The Hedgehog pathway is involved in the development and segmentation of embryos. Therefore if there is a defect at some point with the proteins/ genes involved with a normal adult stem cell, the normal stem cell may transform into a cancer stem cell. Given the fact that this pathway is involved with development, a defect would be identified as a genetic malfunction and appear, but not limited to children. Children with compromised Hedgehog-pathway-components may exhibit cancer in the brain, lung, mammary gland, prostate, and skin. How can one pathway carry such a role in development?
The Hedgehog pathway, under normal conditions, is ligand dependent. A ligand must bind to Patched, transmembrane protein receptor, to activate the phosphorylation of another protein (Smoothened) that plays a role in the Wnt and G-protein-coupled receptors; which are both involved in cell development, but initiate alternate pathways that activate the transcription of specific genes. [1] The interconnection of Hedgehog with these other pathways is how a defect in it may lead to a disruption of cancer in multiple regions of the body. The hedgehog pathway is believed to play a role in 30% of all human malignancies which include pancreatic, gastrointestinal, colorectal, ovarian, prostate, some leukemias, and multiple myeloma.[2]
Developing cancer with a defect in hedgehog pathway does not only occur during embryogenesis. A cancer may result by activating normally silenced hedgehog genes in an adult. Therefore, the fact that drugs are being manufactured to target this pathway covers the challenge of avoiding detrimental effects in normal cells. By correcting the hyper-activation of hedgehog genes the cancerous cells may revert to normal cells. How? Well in the case of vismodegib, the drug is designed to inhibit the activation of Smoothened, the normal function of Patched without a ligand, which prevents the expression of the genes involved in tumor growth. [3]
Therefore, Hedgehog pathway is a promising target to combat cancer. In fact, multiple companies besides Genentech are developing drugs that target some aspect of the pathway. These drugs are in the process of being tested and have been clinically proven to be Hedgehog inhibitors: cyclopamine, and LY2940680. Creating alternative drugs for a common goal is not a waste of resources or time since the more research that is done, the more we understand about the behavior of certain drugs to cancer cells. These alternative drugs can also serve as substitutes to vismodegib which is essential for some patients. A recent study indicated the possibility of some cancer patients exhibiting resistance to vismodegib. This resistance is a pharmacogenomics issue since these patients do not possess genes that code for the metabolism of this drug. This study along with many others elevate the significance of personalized medicine and contribute to the greater debate about privacy issues. Should doctors sequence a patient’s DNA before prescribing treatment to ensure the efficacy of a drug? If so, patients would save numerous trips to the doctor's office and a substantial amount of money. If no, the patient's genetic information is kept private which would eliminate the use of genetic discrimination among insurance companies.
All in all vismoegib and other clinical drugs seem to be the answer to in treating cancer patients. Drug therapy the avenue to identify an ultimate cure as there have not been any cases that I came across that introduced other types of cancer or enhanced the growth of an existing cancer cell type. Patients discussing the type of cancer treatment they would like to endure should consider drug therapy over chemotherapy.
