FLT3 gene mutations play critically important role in acute myeloid leukemia
The key to treating one of the most common types of human leukemia may lie within mutations in a gene called FLT3, according to new research led by physician-scientists at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.
Published this week in the journal Nature, the work validates certain activating mutations in the FLT3 gene as targets for acute myeloid leukemia therapya critically important finding for developing drugs.
"These mutations are critically important for the survival of leukemia cells that harbor them," said Neil Shah, MD, PhD, who led the research, and is co-leader of the Hematopoietic Malignancies Program at the Helen Diller Family Comprehensive Cancer Center at UCSF and the Edward S. Ageno Distinguished Professor of Hematology/Oncology. "Our results also identify drug-resistant mutations in FLT3 that represent high-value targets for future drug development, and will hopefully rekindle interest in developing potent FLT3 inhibitors for the treatment of acute myeloid leukemia."
The new work also suggests why a handful of older drugs developed to treat acute myeloid leukemia by targeting FTL3 have previously failed in clinical trials. The problem with these drugs was not lack of precision but of powerthey were aimed at the right target needed to stop the cancer, but most likely did not hit this target hard enough.
Patients in the future may be better served by therapies that involve combinations of multiple, more potent drugs that can suppress all drug-resistant forms of FLT3, said Shah, whose lab is working to identify such compounds and bring them to the clinic as quickly as possible.
A COMMON AND DEADLY FORM OF CANCER
Acute myeloid leukemia occurs when the precursors of our own blood cells become corrupted by mutations in their DNA. The mutant precursors then fail to produce several critical components of blood: white cells, which fight infections; red cells, which carry the blood's oxygen supply; and platelets, which clog vessels when they are cut and help minimize blood loss.
Instead, the mutant precursors give rise to leukemia cells, which accumulate in the bone marrow and bloodstream, crowding out the healthy blood components, and commonly lead to life-threatening infections, anemia, and bleeding.
Over the last several decades, the five-year survival for acute myeloid leukemia has not improved, even as better diagnostic tests, imaging techniques and treatments have driven down mortality for other forms of cancer. According to the National Cancer Institute, 1 in 256 Americans will be diagnosed with acute myeloid leukemia in their lifetime and today nearly four out of five people with the disease die within five years of their diagnosis.
The goal of therapy is to eliminate cancerous cells altogether from the bone marrow, and the discovery several years ago that many people with acute myeloid leukemia have activating mutations in the FTL3 gene, coupled with the relationship of these mutations to poor prognosis, led scientists to speculate that targeting this mutated gene might be an effective way to fight the cancerbut only if the gene was critically important for the survival of leukemia cells.
Several drugs were tested in the clinic, but failed to put the disease into deep remission. The cause for these failures came down to one of two possible reasons: either the FTL3 gene mutations were not central "drivers" critical for cancer to develop and leukemia cells to survive, or the drugs themselves could not achieve the necessary degree of inhibition of FLT3.
The new work by Shah and his colleagues demonstrates the latter. They worked with eight leukemia patients who participated in a clinical trial involving a compound known as AC220, the first clinically-active FLT3 inhibitor. All eight relapsed after first achieving deep remissions with AC220.
In collaboration with Pacific Biosciences, a Menlo Park, Calif. company, a new sequencing technology was adapted to more sensitively and precisely detect drug-resistant mutations. The team showed that in all eight cases, one or more of these mutations evolved at the time AC220-resistant disease developed.
They are now searching for compounds that can specifically target these mutated, AC220-resistant forms of FTL3, and have identified several promising candidates, one of which is currently being evaluated in a clinical trial at UCSF by Catherine Smith MD, who works in Shah's laboratory and is the first author of the article.
More information: The article, "Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia" by Catherine C. Smith, Qi Wang, Chen-Shan Chin, Sara Salerno, Lauren E. Damon, Mark J. Levis, Alexander E. Perl, Kevin J. Travers, Susana Wang, Jeremy P. Hunt, Patrick P. Zarrinkar, Eric E. Schadt, Andrew Kasarskis, John Kuriyan and Neil P. Shah is published in Nature on 4/15/12. DOI: 10.1038/nature11016
Journal reference: Nature
Provided by University of California, San Francisco
- Two-faced leukemia? Dec 12, 2011 | not rated yet | 0
- Kidney cancer drug attacks a major type of acute myeloid leukemia Jan 29, 2008 | not rated yet | 0
- Cardiovascular drug may offer new treatment for some difficult types of leukemia Sep 12, 2011 | not rated yet | 0
- Study reveals origins of a cancer affecting the blood and bone marrow May 12, 2011 | not rated yet | 0
- Drug makes leukemia more vulnerable to chemo Mar 20, 2012 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be a term called "intestinal metaplasia" of stomach
3 hours ago Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
- More from Physics Forums - Medical Sciences
More news stories
The surgical management of non-small cell lung cancer (NSCLC) in U.S. hospitals varies widely depending on the race of the patient, according to a new study.
Cancer 36 minutes ago | not rated yet | 0
Treatment with an Alpha-1 proteinase inhibitor (A1-PI), a naturally occurring protein that protects lung tissue from breakdown and protects the lung's elasticity, is effective in slowing the progression of emphysema in patients ...
Cancer 59 minutes ago | not rated yet | 0
Scientists from Nanyang Technological University (NTU) and Lund University, Sweden, have bioengineered a novel molecule which has been proven to successfully kill tumour cells.
Cancer 1 hour ago | not rated yet | 0
An article published on the journal Nature describes the major role that Pyruvate dehydrogenase (PDH) —an enzyme of cellular energy metabolism— plays in the regulation of the cellular senescence induce ...
Cancer 1 hour ago | not rated yet | 0
(Medical Xpress)—Scientists at the School of Medicine have shown that their previously identified therapeutic approach to fight cancer via immune cells called macrophages also prompts the disease-fighting killer T cells ...
Cancer 3 hours ago | not rated yet | 0 |
In a remote fishing community in Venezuela, a lone fisherman sits on a cliff overlooking the southern Caribbean Sea. This man –– the lookout –– is responsible for directing his comrades on the water, ...
1 hour ago | not rated yet | 0 |
A novel approach to obstructing the runaway inflammatory response implicated in some types of asthma has shown promise in a Phase IIa clinical trial, according to U. S. researchers.
1 hour ago | not rated yet | 0
Authorities are investigating rice mills in southern China following tests that found almost half of the staple grain in one of the country's largest cities was contaminated with a toxic metal.
1 hour ago | not rated yet | 0
Clinical measurement of physical activity appears to be an independent predictor of whether or not patients with chronic obstructive pulmonary disease (COPD) will end up being hospitalized, according to a new study conducted ...
46 minutes ago | not rated yet | 0
Delayed transfer to the intensive care unit (ICU) in hospitalized patients significantly increases the risk of dying in the hospital, according to a new study from researchers in Chicago.
26 minutes ago | not rated yet | 0
The negative effects of poorly controlled asthma symptoms on sleep quality and academic performance in urban schoolchildren has been confirmed in a new study.
1 hour ago | not rated yet | 0