New Software Identifies and Stratifies Risk Posed by Lung Nodules

Apr. 8, 2013 — A multidisciplinary team of researchers at Mayo Clinic has developed a new software tool to noninvasively characterize pulmonary adenocarcinoma, a common type of cancerous nodule in the lungs. Results from a pilot study of the computer-aided nodule assessment and risk yield (CANARY) are published in the Journal of Thoracic Oncology.

"Pulmonary adenocarcinoma is the most common type of lung cancer and early detection using traditional computed tomography (CT) scans can lead to a better prognosis," says Tobias Peikert, M.D., a Mayo Clinic pulmonologist and senior author of the study. "However, a subgroup of the detected adenocarcinomas identified by CT may grow very slowly and may be treatable with less extensive surgery."

CANARY can noninvasively stratify the risk lung adenocarcinomas pose by characterizing the nodule as aggressive or indolent with high-sensitivity, specificity and predictive values.

CANARY uses data obtained from existing high-resolution diagnostic or screening CT images of pulmonary adenocarcinomas to match each pixel of the lung nodule to one of nine unique radiological exemplars. In testing, the CANARY classification of these lesions had an excellent correlation with the microscopic analysis of the surgically removed lesions that were examined by lung pathologists, Dr. Peikert says.

Lung cancer is the leading cause of cancer-related deaths in the United States.

"Without effective screening, most lung cancer patients present with advanced stage disease, which has been associated with poor outcomes," Dr. Peikert says. "While CT lung cancer screening has been shown to improve patient survival, the initiation of a nationwide screening program would carry the risk of overtreatment of slow growing tumors and would be associated with substantial health care costs. CANARY represents a new tool to potentially address these issues."

 http://www.sciencedaily.com/releases/2013/04/130408133044.htm

GENES IN PROSTATE CANCERS

In a man, there is a 1/3 chances that if found with cancer, it will be prostate cancer.  But only in 10 percent of those who are dying and who have prostate cancer is it this cancer that causes death.  Meaning a number of patients with prostate cancer will die of another cause.   Over 186,000 men were diagnosed with Prostate Cancer and close to 29,000 died of this disease yearly. A 6.5 to 1 ratio.  This point to a heterogeneous disease, and we will fail by not stating (infamous statement) that autopsy showed that in men over 80 years of age, over 70% will be found with Prostate Cancer.  As if it was part of aging.   By aging, you implicate Telomeres and most likely the MTOR.
Before jumping to the MTOR which is cool lately, there is one overwhelming phenomena, that is the Prostatic cell development is significantly dependent on Testosterone for its growth.  And we have in our armamentarium many agents to stop Testosterone.  As we will suggest and as achieved for many hormones, Testosterone blockage can be completed at the cell level, in the testicles, in the Adrenal gland as well as by blocking it in the Pituitary stalk. It is not until one develops refractoriness to Androgen that one may die of Prostate cancer as the principal cause of death.  So the physician's task is to keep coming up with new strategies to block the Androgens.  There lies the key to treating Prostate Cancers.

THE REVERSAL OF FORTUNES
=========================
It is widely accepted that a small numbers of cells in the prostatic cancer mass (may be less than one percent at onset) will be mutated or spontaneously refractory to Androgen.  As time goes by, more mutations related or not to treatment, will occur, while hormone sensitive cancer cells are being starved from stimulation.  Over time, the refractory cells will grow in importance and drive the life of the tumor and metastasize everywhere replacing the hormone sensitive one. The disease will therefore become non responsive to Hormone and here comes patient rapid deterioration as the malignant tumor now adopts a new pattern of behavior including new locations of metastasis.  Liver lesions, lung lesions and Brain invasion becomes more likely to occur.   Chemotherapy with Taxane and Cabazitaxel, a derivative of natural Taxoids, become the mainstay of treatment.  ( Particularly now that Sipuleucel-T  is advanced to before chemotherapy) Keeping in mind that the reversal of fortune is change of proportions, there is still a portion of hormone responsive cells and Lupron needs to continue while chemotherapy is given!

PSA, Prostate Specific Antigen
======================
Prostate cancer is actually one of the rare diseases that can be screened effectively, and found early by a blood test.  That is until we realize that finding a disease that may not kill early leads to unnecessary treatment and patient futile mental disturbance in many cases.  We are now retracting, pulling back on our toes and people are growing reluctant to be tested. That is until we clarify what it is we should be looking for to make sure we discern who needs therapy! We needs to know who needs an early intervention.  For this the tumor needs to tell us I am bad, and we need to catch the message.  And most researchers believe Genetic profiling is one of the critical approaches  to tell the difference. The challenge is that Adenocarcinoma seems to follow a progression in their deterioration to a full blown cancer.  And some genes are present in prostatitis, Benign Prostatic hypertrophy, Low Gleason prostatic cancer and high gleason cancers.   Now which one makes it a bad cancer.  This is the current challenge but it will clearly open the door to Target therapy!

Molecular basis of Prostatic cancer Pathogenesis.

While dealing with Intraepithelial Atypical lesion, the presence of Alpha-Methylacyl-Coenzyme Aracemase is considered a signature of Adenocarcinoma presence!   In our discussion on Choriocarcinoma, we suggested that Hypermethylation is a major Knockdown way for E2.  It plays a role here too!   And gene fusion is the other abnormality that is a prominent phenomenon TMPRSS2 and ETS fusion (or TMPRSS2-ERG), and things" degenerate" from there !

Also note that the Androgen receptor gene is located on Xq11-13, (note the "q")

GENES in Prostate Cancers! (TO BE DEFINITELY CONTINUED)

TODAY'S CONFERENCE NEWS!

One thing is for sure: current clinical practice of Oncology is miles away from the cutting edge science advancing before it and there is a reason to this fact, only what is clearly established and approved by national institutions reaches the practicing Oncologist.  And clearly, it is important that speakers during Oncology conferences reinvent themselves deep enough to understand the flow of information coming through.  It is easy to tell who knows fully and who is trying to keep up among speakers.   Navigating the world of research while keeping up with clinical studies is the challenge our speakers face.

1.  In lung cancer
-------------------
*In Adenocarcinoma:  Pemetrex +Cisplatin based treatment is still King prior to gene Mutation determination, in Metastatic setting and first line
*But when EGFR and positive is known, Erlotinib came on top! And when progression occurs,
continuing ERLOTINIB, but adding a chemotherapy doublet won!
*Despite great achievements by Target therapy in lung cancer, most of the time it is hard to prove survival benefits because most studies allow cross-over of those failing the chemotherapy-alone arm.
*Afatinib was superior to Cisplatin-Pemetrex in those with Del 19/L858R (EGFR mutation positive)
with Progression free survival 13.6 months Vs 6.9 months in metastatic setting.
*Increasingly, re-biopsy at recurrence is occurring to reassess the status of common Mutations.
It has noted that tumors which were EGFR positive, once they become resistant, they adopt small cell features and respond to Small cell regimens.
* When using a EGFR, continue the drug beyond resistance because in a limited MSKCC series, up to 25% of cancers experience a "FLARE" when TKI (Tyrosine Kinase Inhibitors) were discontinued.  So, while considering options for 2nd line therapy, do not stop TKI.

*Currently tested Mutations:
EGFR, EML4-ALK fusion, MET amplification by FISH (not so much by IHC), ROS-1, PIK3CA (sometime FGFR1)
*"PROXIMITY" TO ROS1 WITH INSULIN RECEPTOR discussed
*IF EGFR positive, rarely you will find KRAS (exclusivity rule discussed)
*in lung cancer :
you find ROS1 in 1.5% of cases,
             ALK + in 5% of cases
             RET + in 2% of cases
             EGFR + in 18% of cases
             HER-2 in 2 % of cases
*Acinar Morphology a cue for ALK positive? and CRIZOTINIB is the answer!

*Now comes OR HAS ARRIVED THE PRACTICE OF "MULTIPLEX TESTING" FOR IDENTIFICATION OF SPECIFIC MUTATIONS.
*Of note: the study showing Taxotere equivalent to Gefitinib in lung cancer cases unscreened for EGFR mutation at onset of trial are challenging the notion of Early EGFR identification!

NEW GANETESPID (+TAXOTERE), THIS IS AN INHIBITOR OF HSP90, A CHAPERONE MOLECULE AND PD-L1   BMS936558

WITH THIS FRAME OF INFORMATION - GO TO WORK!

NEXT: METASTATIC MELANOMA

WE WANT TO SEE YOU THERE

New and Improved for 2013 Interactive and educational, Great Debates and Updates in GI Malignancies will focus on controversial areas in the management of gastrointestinal malignancies as nationally-recognized thought leaders take opposing sides on topics of clinical interest. Located conveniently in New York City, discussions at Great Debates and Updates in GI Malignancies this year will include: • Clinical update and novel therapies for hepatocellular carcinoma • Genetics and GI cancers – How genetics are helping us identify, predict and decrease risk as well as determine new therapeutic targets • What is the optimal chemoradiotherapy for locally advanced, unresectable esophageal and GE junction adenocarcinomas? • Is there hope on the horizon for KRAS-mutant tumors and for BRAF-mutant tumors in the management of colorectal cancer? For more information, visit the conference website: imedex.com/gi-malignancies-debate-conference/

MORE INFORMATION REGISTRATION Early Registration Deadline March 14, 2013 Presentation Dates April 5-6, 2013 Location New York, NY Westin New York at Times Square Conference will feature ARRAY technology - bring your laptop or tablet and participate with the most up-to-date information

A WELL STUDIED MOLECULE!

BUTEIN

1. It is a natural Chalconoid, derived from Toxicodendron Vernicifluum
2. It is inhibitor of EGFR and SRC Tyrosine Kinase, Please give it in all Adenocarcinoma ...(in a trial of course! and at your own expenses and risk!)
3.Inhibitor of c-AMP dependent processes
4. Induce Apoptosis in B16 Melanoma cells and in HL60 Leukemia cells.
5. Anti-inflammatory
6. An Aldolase Reductase
7. An Aromatase inhibitor, please give it in ER positive Breast Cancer
8. a chelator of Iron and Cupper, please give it in Hemosiderosis in a clinical trial
9. Inhibitor of NF-kB and TNF inhibitor, that's how it is an anti-inflammatory
(try it in Sepsis gone overboard-in clinical trial). MD Anderson claimed it does this by Inhibiting IKK, check it out!
10. Activator of Sirtuins, the stuff you give to stop Dementia!  Sirtuins that you take to preserve survival through Telomere protection.  Oh by the way Sirtuins are Histone Deacetylators!  do the math and consequence calculation.  It will add to the MTOR inhibitors!
11, Increase activity of Caspase 3, Increase activity of BAX, and decrease BCL-2 to lead to Apoptosis of cancer cells talked about above!
12. Inhibitor of Glutation reductase

Please I have to stop here,  These are just too much goodies!
I will be taking this Butein myself!
I guess you can relax now!
Believe me, people take Butein to treat their Gastric Cancers even!

WAKE UP AND SMELL THE COFFEE.  THE STORY OF DDR2

ONE OF THE MOST POWERFUL PAPERS

« ASCO issues Provisional Clinical Opinion on EGFR testing in Non-Small-Cell Lung Cancer | Main | Systems biology for studying cancer »

May 06, 2011

DDR2 Kinase Mutations in Lung Squamous Cell Carcinoma

Yes--you read that right!
The journal Cancer Discovery reports in a publish ahead-of-print article (abstract) the discovery of mutations in the discoidin domain receptor 2 tyrosine kinase (DDR2) gene in a series of lung squamous cell carcinomas (SQC) that may identify a  potential therapeutic target similar to those described for lung adenocarcinomas.  Interestingly, DDR2 is a receptor kinase that normally binds collagen as its ligand and has been shown to promote cell migration, proliferation, and survival when activated by ligand binding and phosphorylation.
While subtypes of lung adenocarcinoma (ADC) have been increasingly better defined and characterized on multiple levels with respect to identifying therapeutic targets/responses, minimal progress has been made with squamous cell carcinoma.
The authors of this study used conventional Sanger sequencing of 201 genes, including the entire tyrosine kinome, in an initial set of 20 primary lung SQC and matched normal controls and identified 2 samples with DDR2 mutations; a secondary screen of 48 lung SQC samples identified an additional 4 DDR2 mutations.  Following this, the authors sequenced DDR2 in a validation cohort of 222 primary lung SQC samples and identified 5 additional samples with mutations.  Excluding samples from lung SQC cell lines, there was an overall frequency of 3.2% of DDR2 mutations in primary lung SQC samples--about the same frequency reported for ALK fusion mutations in lung ADC.
The authors analyzed the TKIs imatinib and dasatinib, previously reported to inhibit DDR2, to evaluate whether targeting DDR2 mutated in SQC might be a potential therapeutic strategy.  Dasatinib showed particular efficacy in inhibiting proliferation and promoting cell death through apoptosis in SQC cell ines with DDR2 mutations.  In addition, they report one of 7 subjects from an early-phase trial of dasatinib or combination dasatinib and erlotinib with advanced stage lung SQC cancer who exhibited significant shrinkage in tumor size while receiving the dasatinib/erlotinib combination.  The authors were able to perform direct sequencing of DDR2 in a pretreatment tumor specimen from this individual and identified a novel DDR2 kinase mutation.
This is an intriguing paper that you might well keep in mind.  Hopefully, this may stimulate other investigators to not only look for other potential genomic alterations that either drive SQC and/or represent targetable proteins but also go back and scrutinize histological and other clinicopathological characteristics of lung SQC that may have therapeutic or prognostic importance.

Posted at 11:40 AM in Lung Cancer, Lung Squamous Cell Carcinoma, Molecular Pathology, Prognostic/Predictive Cancer Markers | Permalink

Reblog (0) | Tweet This!

TrackBack

TrackBack URL for this entry:
http://www.typepad.com/services/trackback/6a010536c71c0f970c014e8846efa5970d
Listed below are links to weblogs that reference DDR2 Kinase Mutations in Lung Squamous Cell Carcinoma:

AT CRBCM WE BELIEVE

ONE OF THE MOST POWERFUL TREATMENT AGAINST A DISEASE IS TO FIND THE TARGET THAT INITIATED IT.  THE STRONGEST EVIDENCE THAT A TARGET MOLECULE IS A CRITICAL MOLECULE IS WHEN ITS MUTATION SHORTENS A LIMB IN INDIVIDUALS AND DDR2 MUTATION DOES EXACTLY THAT !!!!
It reminds me of the story of Thalidomide.  And the 2 can be linked.  I am only 50% of this! And whenever a limb is missing, your Angiogenesis and Differentiation are not very far and sure enough, Dasatinib, Imitanib and most likely Thalidomid are not far, lurking in the neighborhood!

SPONDYLO META EPIPHYSEAL DYSPLASIA (SMED) IS THE CONDITION OF SHORT STATURE AND SMALL LIMBS THAT IS RELATED TO DDR2 MUTATION!
SCIENTISTS DID NOT SLEEP, THEY LOOKED IN LUNG CANCER WHAT DASATINIB WOULD DO IN THESE PATIENTS WITH DDR2 MUTATION AND SURE ENOUGH, DASATINIB WORKS. The proof of concept is there in the pudding.

Now don't go out hunting for any short stature individual to test their gene.  But nature has given us a clue that all short stature gene found in a cancer cell, should not only tell us that the gene is targetable by an anti-VEGF and related kinase.  WE SHOULD BE TESTING ALL CANCER FOR DDR2, AND TREAT WITH DASATINIB. CURE IN THOSE CASES IS REACHABLE!  And may be we can prevent all stature with these drug.   One thing for sure, let's find DDR 2 in triple negative breast cancer, and we know what to give pronto now!