Cancer Treatment Pinpoints Same Genetic Mutation, Arising From Disparate Tissues

choi

Gina Kolata, Fast Way to Try Many Drugs on Many Cancers. New York Times, Feb 26, 2015 (front page, central)
www.nytimes.com/2015/02/26/healt ... celerate-hopes.html

Quote:

"Chemotherapy and radiation failed to thwart Erika Hurwitz’s rare cancer of white blood cells. So her doctors offered her another option, a drug for melanoma. The result was astonishing. Within four weeks, a red rash covering her body, so painful she had required a narcotic patch and the painkiller OxyContin, had vanished. Her cancer was undetectable. * * * In Mrs Hurwitz’s case, the mutation in her rare cancer is in a gene, BRAF, found in about 50 percent of melanomas but rare in other cancers. She is among dozens of patients with the same mutation, but different cancers, in the new study that gives everyone the melanoma drug that attacks the mutation."

“The studies of this new method, called basket studies because they lump together different kinds of cancer, are revolutionary, much smaller than the usual studies, and without control groups of patients who for comparison’s sake receive standard treatment. * * * And they are seeing some unprecedented responses, along with some failures. The responses, though, can be so striking that control groups might be unwarranted or infeasible, Dr [Richard] Pazdur[, an FDA official,] said. 'Conventional therapy might give a response rate of 10 or 20 percent,' Dr Pazdur said. 'The newer drug has a response rate of 50 or 60 percent. Does it make sense to do a randomized trial?' * * * The new studies pose new problems. With no control groups, the effect has to be enormous and unmistakable to show it is not occurring by chance. When everyone gets a drug, it can be hard to know if a side effect is from the drug, a cancer or another disease.

“Doctors around the country will be sending tumor samples from at least 3,000 patients to central labs that will examine them for mutations. Those with any of a dozen or so mutations in their tumors can enroll in studies of drugs that target their tumor’s mutation.


Note:
(a) The name of Mrs Hurwitz’s disease, which is not necessarily a cancer (see (c)(i)), is disclosed at the end of the report.
(b) histiocyte
en.wikipedia.org/wiki/Histiocyte
(histio, diminutive of histo, [with the latter] meaning tissue, and cyte, meaning cell; section 2.2 Langerhans cells)

The takeaway is that monocytes mature into macrophages (which devour various objects (bacteria, viruses etc), and that histiocytes are similar to macrophages.

(c) What is Langerhans cell histiocytosis?  
(i) Genetics Home Reference (a website of National Library of Medicine), undated
ghr.nlm.nih.gov/condition/langerhans-cell-histiocytosis
(excess immature Langerhans cells usually form tumors called granulomas; not generally considered to be a form of cancer; often diagnosed in childhood, usually between ages 2 and 3, but can appear at any age; may even disappear on its own, especially if the disease occurs only in the skin)
(ii) General Information About Langerhans Cell Histiocytosis (LCH). In Langerhans Cell Histiocytosis Treatment (PDQ®). National Cancer Institute, undated
www.cancer.gov/cancertopics/pdq/ ... hProfessional/page1

Quote:

“The histiocytic diseases in children and adults include three major classes of disorders. Only Langerhans cell histiocytosis (LCH), a dendritic cell disorder, is discussed in detail in this summary. Erdheim-Chester disease (primarily found in adults) and juvenile xanthogranuloma (diagnosed in children and adults) are macrophage disorders.

“The term LCH cells is used because there are clear morphologic, phenotypic, and gene expression differences between [normal] Langerhans cells of the epidermis (LCs) and those in LCH lesions (LCH cells).

“The recent discovery that approximately 60% of LCH biopsy specimens demonstrate the V600E mutation in the BRAF oncogene, regardless of stage or organ involvement, has led to the conclusion that LCH is a clonal neoplastic disorder. The same mutation has been found in other cancers, including malignant melanoma; however, V600E-mutated BRAF is also present in benign nevi, possibly indicating the need for additional mutations to render the cell malignant. This finding has raised the possibility of future targeted therapy with inhibitors already in use in melanoma, and several trials of BRAF inhibitors are open in adults and children with BRAF V600E mutated tumors, including LCH. Regardless of having a BRAF V600E mutation, nearly all lesions have been reported to show evidence of activated ERK downstream of BRAF

(A) PDQ®
www.cancer.gov/cancertopics/pdq
("(Physician Data Query) is NCI's comprehensive cancer database")

PDQ is for physician, so very technical, not easily understood by laypersons.
(B) “the V600E mutation in the BRAF oncogene = the 600th amino acid 胺基酸 changes from valine (whose one-letter symbol is “E”) to glutamate (one-letter symbol: E).  The 600th amino acid in what protein 蛋白質?  B-raf (which in humans is made up of 766 amino acids).
(C) Raf kinase
en.wikipedia.org/wiki/Raf_kinase
(RAF is an acronym for Rapidly Accelerated Fibrosarcoma; The three RAF kinase family members are: A-Raf, B-Raf and C-Raf)
(D) ERK = Extracellular-signal-Regulated Kinases
(E) If you do not understand (B) to (D), it is all right. One needs a PhD in biology to understand it.

There is no difference between notations of BRAF (italics or not) and B-Raf.

choi

(d) What is the name of the drug that all patients in this report (including Mrs Hurwitz) receive?  It is RO5185426/vemurafenib/Zelboraf--different names of the same drug, the first was used in the initial stage.
(i) Vemurafenib
en.wikipedia.org/wiki/Vemurafenib
(Vermurafenib is INN (for International Nonproprietary Name); marketed as Zelboraf; The name "vemurafenib" comes from V600E mutated BRAF inhibition)

Please view the chemical structure at upper right corner.
(ii) ZELBORAF—Inhibiting a key driver of melanoma. Genentech and Daiichi-Sankyo 第一三共株式会社, undated (under the heading "Mechanism of action")
www.zelboraf.com/oncology/moa
("ZELBORAF binds [intracellularly] to some forms of mutated BRAF, including V600E, and renders the oncogenic protein inactive")
(iii) Press release: DOE Laboratories Help Develop Promising New Cancer Fighting Drug, Vemurafenib; Powerful X-Rays Enable Development of Successful Treatment for Melanoma and Other Life-Threatening Diseases. US Department of Energy, Aug 18, 2011
energy.gov/articles/doe-laboratories-help-develop-promising-new-cancer-fighting-drug-vemurafenib
(Researchers from Plexxikon Inc, the drug discovery company that developed the melanoma treatment, used X-ray light sources at three national laboratories –SLAC National Accelerator Laboratory, Argonne National Laboratory and Lawrence Berkeley National Laboratory–to determine the specific, 3-D protein structure of a mutated enzyme that tells melanoma cancer cells to multiply uncontrollably. The researchers used a technique called 'macromolecular X-ray crystallography' to develop a drug that would prevent the [mutated] enzyme from doing this")