Friday, October 24th, 2008
In a recent blog, I noted that the CEO of ImClone said KRAS testing has grown substantially since the announcements earlier this summer linking mutations in KRAS with resistance to Erbitux and Vectibix therapies. We may now have to add mutations in BRAF as well, in order to get a more comprehensive view of whether a patient will benefit from these therapies.
A study presented this week at the annual EORTC meeting in Geneva showed that patients with a mutation in the BRAF gene also do not benefit Erbitux or Vectibix. So far, these clinical observations fit perfectly with what we know about the biology of the EGFR pathway. Because KRAS lies downstream of the EGFR, activating mutations in KRAS would be expected to override any inhibition of the EGFR that occurs upstream. Similarly, BRAF lies downstream of KRAS, so activating mutations in BRAF would also be expected to override any inhibition of the EGFR that occurs upstream as well. The study (of 113 patients) found that KRAS and BRAF mutations were mutually exclusive, suggesting that a BRAF mutation is as sufficient as a KRAS mutation in mediating resistance to these therapies, although larger studies would be needed to truly determine this. If these observations fit so well with the biology of EGFR – KRAS – BRAF signaling, you might wonder why it took so long to figure it out (given that we’ve understood these pathways for a quite a long time). To be sure, hindsight is always 20/20, but studies on patient specimens are immensely more challenging than pre-clinical studies, and only in the last several years have more sensitive methods of sequencing and mutation detection come about that can really pinpoint mutations in clinical specimens, where the DNA is generally of poor quality and also may be limiting if only small amounts of tumor are present in a specimen.
So it looks like we may need to test colon cancer patients for both KRAS and BRAF together. While the exact frequency of BRAF mutations in colorectal cancer is not yet known, it is probably at least 10% and perhaps as high as 25%. So even being conservative, we can probably say that almost half (and possibly more) of colon cancer patients will have either a KRAS or BRAF mutation. This is another step forward for personalized medicine since more patients can be put on therapies sooner that will have a real chance of helping them.
At TMD, we’ve been ahead of the curve, by providing the KRAS Mutation test since earlier this year, and also validating the BRAF Mutation test, as we expected that it was only a matter of time before BRAF was found to be important as well. The BRAF Mutation test we use employs the same highly sensitive technology as the KRAS Mutation test. Please contact us to find out how we can provide both KRAS and BRAF testing.
Posted in Biomarkers, Companion Diagnostics, General, Targeted Therapy Development | No Comments »
Monday, September 29th, 2008
New data presented at the Molecular Diagnostics in Cancer Therapeutic Development meeting from investigators at Wyeth shows that the Src pathway may play a role in resistance to some breast cancer therapies. Src is an enigmatic player in cancer. Despite being one of the oldest known oncogenes and having potent transforming capabilities in chicken cells, Src’s exact role in human cancer has remained somewhat elusive. The new research indicates that high activation of the Src pathway is often seen in tumors that are estrogen receptor, progesterone receptor and HER2 negative (so called “triple negative breast cancer”). Patients with high levels of Src pathway biomarkers were generally correlated with lower overall survival.
Because there are now Src inhibitors in clinical trials, this finding raises the intriguing possibility that current breast cancer therapies could be combined with Src inhibitors to augment the action of breast cancer therapy or perhaps decrease the chance of a patient developing resistance. At TMD, we’ve been involved with the clinical development of Src inhibitors and have many bioamarkers to interrogate the activation state of the Src pathway such as phospho-Src, phospho-FAK and phospho-paxillin, to name just a few. These biomarkers can be performed in real time and used to guide patient therapy or can be part of larger biomarker strategy for a retrospective study analysis. Please see the biomarker section of website for a complete list of our validated biomarkers. We also offer a full range of clinical development services.
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Thursday, September 18th, 2008
A recent study published in Molecular Cancer Research found an association between the expression of a histone deacetylase, SIRT1, and resistance to cisplatin. Cells that were initially sensitive to cisplatin were made resistant to the drug by continuous exposure. The researchers found high levels of SIRT1 in the resistant lines. Reducing the levels of SIRT1 made the cells more sensitive to cisplatin again. This study was conducted at the NCI. Although this is an early study performed in cell lines in the laboratory, it is important because while a great deal of effort goes into discovering biomarkers for targeted therapies, there has not been a lot of focus on finding biomarkers for traditional chemotherapies, like cisplatin-based drugs.
TMD has validated immunohistochemistry (IHC) assays for the detection and measurement of SIRT1 and SIRT2 in tissue. They can be used for pre-clinical development work such as xenograft studies or for clinical development in human tissue. Please contact us for more information about our SIRT1 or SIRT2 assays.
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Thursday, January 10th, 2008
EGFR inhibitors have faced a difficult road in finding biomarkers that would select patients to receive the drugs. Unlike its close sibling, ErbB2, in which amplification or over expression is a prerequisite for treatment with trastuzumab or lapatinib, the expression of EGFR (or lack of) has consistently shown no correlation with clinical outcome.
Patients with mutations in the EGFR do often respond better to EGFR targeted TKIs (like gefitinib and erlotinib) but this generally does not translate into increased survival. Amplification of EGFR may emerge as a predictive factor, although this issue remains somewhat murky because the interpretation of EGFR amplification is considerably more complex than ErbB2.
Recently in a Phase III analysis of panitumumab (http://www.medscape.com/viewarticle/563710) and a Phase II analysis of cetuximab (http://jco.ascopubs.org/cgi/content/abstract/25/22/3230) in metastatic colorectal cancer, the presence of a K-Ras mutation in a patient’s tumor was significantly associated with lack of response and disease control. It should be noted that these trials studied the drugs as monotherapies.
These studies highlight the importance of looking downstream of any given target. Since EGFR signals through the Ras pathway, mutations that constitutively activate Ras most likely cause a tumor cell to not see the EGFR inhibitor.
Tests to identify mutations are more complex and time consuming than traditional immunohistochemistry or in situ based tests. TMD offers a K-Ras mutation assay that detects the 7 most common K-Ras mutations in the Gly12 and Gly13 hotspots. Because this test does not rely on sequencing, the turnaround time can be as little as 3 – 4 days, so that patients could be screened prior to randomization in a clinical trial. TMD can perform this test from formalin fixed paraffin embedded clinical specimens. Does our approach make sense? Would this be a test that you would like to see? Any suggestions?
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Wednesday, November 28th, 2007
Numerous companies have incorporated biomarkers as part of their therapeutic development strategy. Although widely discussed, there are only a few examples where the strategy is successfully implemented. SuperGen appears to have a promising example by analyzing the RAD51 biomarker, a DNA repair molecule, in its Phase I trial of MP470, a multi-targeted tyrosine kinase inhibitor. Most tumor cells use DNA repair pathways to repair the single- or double-stranded breaks created by radiation and chemotherapeutic agents. Patients with lower expression levels of RAD51 appear to be most sensitive to combinations therapies that incorporate MP470. TMD (www.tmdlab.com) developed the immunohistochemistry test for RAD51 that is used in the SuperGen trial. The test is also being used for the development of erbB1/erbB2 tyrosine kinase inhibitors. We continue to develop such tests with the lofty objective of accelerating the development process by enriching patient populations.
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