ASIDE FROM THOSE INCORPORATED IN THE GUIDELINES OF ONCOLOGY PRACTICE
1.EGFR
2.ALK
Now we are hearing about the following
1.ROS-1
2.MEK-1
3.RET
4.BRAF
5.HER-2
6.PI3KCA
7.KRAS
8.PD-1,2
9.ERCC1
10.BRCA-1 mRNA
11 P53
What about the therapeutic roles of :
GSTM-1 and GSTT1,FAK, Wnt, Notch, p16,
HIF and VGEF and the CYP1A1,P ?
Showing posts with label KRAS. Show all posts
Showing posts with label KRAS. Show all posts
Thursday, November 14, 2013
Tuesday, March 19, 2013
Ovarian Cancer
*Researchers who conducted the study who conducted the use of Selumetinib in low grade serous Ovarian cancer were still puzzled because its activity did not follow presence of KRAS or BRAF. They have been wondering if it used another pathway. But remember MEK is the revolving door to de-differentiation and to the reversal of mesengialization and as such increase tor susceptibility not only to chemotherapy drugs, but also to the secondary angiogenic potentiation of MEK. That is, with anti-MEK, there is a down regulation of MAPK (as suggested) and therefore the C-JUN and TGF and cyclins, but also down regulation of the VEGF!
They say " Our results suggest that selumetinib is an active agent, but not necessarily because of BRAF or KRAS mutational activation per se,” the authors concluded.
They say " Our results suggest that selumetinib is an active agent, but not necessarily because of BRAF or KRAS mutational activation per se,” the authors concluded.
In an interview, Gershenson said that one reason for the
lack of correlation could be biomarker instability. Among the 52
patients, specimens were available for only 40, mutational analysis was
done in 34, and in 28 of those the tissue was from the primary therapy
and not from the recurrent tumor. “The question arises, are these
biomarkers stable over time or do they change, so that what you find in
the primary tumor may not be what you find in the recurrent tumor,” he
said." They suggesting here that the lack of correlation could be due to a changing nature of Biomarker. But the existence of other factors and pathways could not be be excluded!
Gene-Expression Profiling May Help Select Best Drugs for Pancreatic Cancer
MUTATION IN "p" IN A CHROMOSOME IS GOOD FOR YOU!
To further confirm that "p" is better that "q", I went back to see what is the mutation in a curable cancer and germ cell tumors or testicular cancer. And guess what? It is not 12q that is abnormal in testicular cancer, IT IS INDEED 12p that is involved in the Malignant transformation.
CCND2 is at 12p13, but also SOX5, JAW1, and KRAS is at 12p11.2-12.1
You know angry corresponding family members are located on other chromosomes, but not amplified in Testicular cancer and would confer resistance to therapy. In fact it would be interesting to see if they are amplified in refractory cases for proof of concept!
The association with endoreduplication (Multiple ploidies) is another good thing to look into further as it relates (or not) to 12p Mutation!
Certainly the response to chemotherapy alone is an intriguing phenomena by itself and should open up cues to look for in other cancers! I believe it is in the "p" and in the "ploidy" thing or tendency to multiply that is where the cancer vulnerability is squarely located!
CCND2 is at 12p13, but also SOX5, JAW1, and KRAS is at 12p11.2-12.1
You know angry corresponding family members are located on other chromosomes, but not amplified in Testicular cancer and would confer resistance to therapy. In fact it would be interesting to see if they are amplified in refractory cases for proof of concept!
The association with endoreduplication (Multiple ploidies) is another good thing to look into further as it relates (or not) to 12p Mutation!
Certainly the response to chemotherapy alone is an intriguing phenomena by itself and should open up cues to look for in other cancers! I believe it is in the "p" and in the "ploidy" thing or tendency to multiply that is where the cancer vulnerability is squarely located!
Sunday, March 10, 2013
METASTATIC COLON CANCER
*It is interesting to note that in current clinical practice 3/4 of Oncologist still give Avastin instead of Cetuximab as their first choice in KRAS wild type metastatic colon cancer, and they chose it in combination with FOLFOX. Why to do the test at onset. And 12 cycles won rather than "until disease progression" in Metastatic setting.
* If you worry about Mismatch repair, it did not come up!
*Avastin-Xeloda superior to Xeloda alone with
- progression free survival (PFS) 9.1 months Vs 6.1months
- Overall survival (OS) 20.7 months Vs 16.8 months
* In Maintenance setting, Combining Avastin to Erlotinib was superior to Avastin alone (OPTIMOX3) in terms of progression free survival.
*In the VELOUR study
Aflibercept +FOLFIRI was superior to Folfiri alone in terms of PFS and OS.
*new kid on the block Regorafenib (brings back use of EUCERIN cream for patients palms)
* If you worry about Mismatch repair, it did not come up!
*Avastin-Xeloda superior to Xeloda alone with
- progression free survival (PFS) 9.1 months Vs 6.1months
- Overall survival (OS) 20.7 months Vs 16.8 months
* In Maintenance setting, Combining Avastin to Erlotinib was superior to Avastin alone (OPTIMOX3) in terms of progression free survival.
*In the VELOUR study
Aflibercept +FOLFIRI was superior to Folfiri alone in terms of PFS and OS.
*new kid on the block Regorafenib (brings back use of EUCERIN cream for patients palms)
Thursday, March 7, 2013
NEWS from ASCO
*Avastin-Folfoxiri better than Avastin-Folfiri, no news there. It is just a repeat of things we knew would happen.
*In Colon cancer patients with Wild type KRAS Panitumumab (Vectibix) associated to 5-FU based combination gave an outcome comparable to results obtained in a different study with Avastin and 5-FU based combination. 2 phase II trials but 2 similar outcomes. And this in first line and 2nd line. Can't wait to see a phase III.
*40% Glioblastoma express EGFR
20% have EGFRvIII
with Lapatinip being looked at for treatment, will wait to see.
*In Colon cancer patients with Wild type KRAS Panitumumab (Vectibix) associated to 5-FU based combination gave an outcome comparable to results obtained in a different study with Avastin and 5-FU based combination. 2 phase II trials but 2 similar outcomes. And this in first line and 2nd line. Can't wait to see a phase III.
*40% Glioblastoma express EGFR
20% have EGFRvIII
with Lapatinip being looked at for treatment, will wait to see.
Sunday, February 24, 2013
NOMENCLATURE OF GENES TO LOOK FOR IN TRIPLE NEGATIVE BREAST CANCER
One may try to determine whether a breast cancer has bad prognosis in order to determine whether chemotherapy should be given (MammaPrint, Oncotypr DX), but more importantly, I believe, is to focus on genes of good prognosis which include driver genes against which we dispose of an answer in our Arsenal.
Currently we dispose of
1. Chemotherapy that attacks DNA and Microfilament/Microtubules, (first and second law of nature)
2. Immune Modulators such as Interferon
3. Antibody to Membrane Receptor (EGFR/VEGF) Avastin
4. Inhibitor to T-cell driven immunity (CTLA4)
5. Inhibitors to sub-membrane or first line driver Mutations KRAS, HRAS, or the RAS family
6. Inhibitors to 2nd line driver Mutations (anti MEK)
7. Inhibitor to Tertiary line driver Mutations and Mitochondrial level inhibition (MTOR, Metformin)
8. Anti-proteasome or inhibitor to cellular protein degradation (Velcade)
9. Inhibitors at Nuclear lever Include Histone Deacethylator and Acyl transferase inhibitor, check point controller inhibitors, anti-Centrosome metabolism and inhibitors of various promoters and transcription factors.
Other opportunities not included in this classification go to specific genes of proliferation, Amplification, differentiation and metastasis that have been brought forth as indicator of either response to chemotherapy or simply as "Good prognosis" genes. These will include the BRCA since a response to PARP inhibitors and Cisplatin based combinations should be anticipated.
Multikinase inhibitors such as Dasatinib (SRC+ BCR/ABL but also STAT5) and Arsenic Trioxide should be included
LBK1: could predict early disease (inhibitor controlling initiation of metastasis)
DDR2: could predict anti MEK sensitivity
MEKK-1 sensitivity to Cisplatin
TFF1-could predict sensitivity to estrogen despite negative Estrogen
DYRK2, favorable in lung cancer
c-JUN amplification and over expression of 8q23-24 could predict response to interferon/Interleukin
EGFR, VEGF, ALK, and other Driver Mutations would match those discussed By DR Kris in lung cancer.
(to be continued!)
Currently we dispose of
1. Chemotherapy that attacks DNA and Microfilament/Microtubules, (first and second law of nature)
2. Immune Modulators such as Interferon
3. Antibody to Membrane Receptor (EGFR/VEGF) Avastin
4. Inhibitor to T-cell driven immunity (CTLA4)
5. Inhibitors to sub-membrane or first line driver Mutations KRAS, HRAS, or the RAS family
6. Inhibitors to 2nd line driver Mutations (anti MEK)
7. Inhibitor to Tertiary line driver Mutations and Mitochondrial level inhibition (MTOR, Metformin)
8. Anti-proteasome or inhibitor to cellular protein degradation (Velcade)
9. Inhibitors at Nuclear lever Include Histone Deacethylator and Acyl transferase inhibitor, check point controller inhibitors, anti-Centrosome metabolism and inhibitors of various promoters and transcription factors.
Other opportunities not included in this classification go to specific genes of proliferation, Amplification, differentiation and metastasis that have been brought forth as indicator of either response to chemotherapy or simply as "Good prognosis" genes. These will include the BRCA since a response to PARP inhibitors and Cisplatin based combinations should be anticipated.
Multikinase inhibitors such as Dasatinib (SRC+ BCR/ABL but also STAT5) and Arsenic Trioxide should be included
LBK1: could predict early disease (inhibitor controlling initiation of metastasis)
DDR2: could predict anti MEK sensitivity
MEKK-1 sensitivity to Cisplatin
TFF1-could predict sensitivity to estrogen despite negative Estrogen
DYRK2, favorable in lung cancer
c-JUN amplification and over expression of 8q23-24 could predict response to interferon/Interleukin
EGFR, VEGF, ALK, and other Driver Mutations would match those discussed By DR Kris in lung cancer.
(to be continued!)
Wednesday, February 20, 2013
A PEEK INTO THE FUTURE!
The article published in the Lancet about Taxotere combined to Selumetinib in 2nd line treatment of lung cancer, opens the door to future therapy to come. It marks the increasing trend of incorporating Target therapy to standard good old chemotherapy. Selumetinib is a MEK inhibitor downstream from KRAS.
Already the results are impressive with the doubling of progression free survival and Overall survival.
Already, we have a peek to a new set of toxicity because these are new combinations and the outlook is grim now with almost half of the patients having Nausea, diarrhea, severe Neutropenia and stomatitis.
Not only is MEK down stream from RAS-RAF-MEK-ERK (MAPK) signaling pathway; it is the revolving door between epidermal presentation which should block Metastatic spread and Endodermal transformation that the Cancer chooses to metastasize.
Another question that will rise immediately is if we have a driver mutation, when should we stop inhibiting such target, when do we stop closing this revolving door? The rising need of maintenance therapy follows. In lung cancer, Alimta, Tarceva and Taxotere have all shown to be beneficial in maintenance setting. So the choice here would be Taxotere maintenance, or should we continue to push closed MEK with Selumetinib?
This article emphasized the fact that this was the first time that KRAS was used as a biomarker for Target therapy. Very true, but mesenchymal transformation and angiogenesis play a role in almost every cancer.
THE FIGHT IS ON.
(LAST POINT: WE HAVE NOT LEARNED ENOUGH ABOUT HOW TO PREVENT THESE SIDE EFFECTS, WE NEED TO STEP UP!)
The article published in the Lancet about Taxotere combined to Selumetinib in 2nd line treatment of lung cancer, opens the door to future therapy to come. It marks the increasing trend of incorporating Target therapy to standard good old chemotherapy. Selumetinib is a MEK inhibitor downstream from KRAS.
Already the results are impressive with the doubling of progression free survival and Overall survival.
Already, we have a peek to a new set of toxicity because these are new combinations and the outlook is grim now with almost half of the patients having Nausea, diarrhea, severe Neutropenia and stomatitis.
Not only is MEK down stream from RAS-RAF-MEK-ERK (MAPK) signaling pathway; it is the revolving door between epidermal presentation which should block Metastatic spread and Endodermal transformation that the Cancer chooses to metastasize.
Another question that will rise immediately is if we have a driver mutation, when should we stop inhibiting such target, when do we stop closing this revolving door? The rising need of maintenance therapy follows. In lung cancer, Alimta, Tarceva and Taxotere have all shown to be beneficial in maintenance setting. So the choice here would be Taxotere maintenance, or should we continue to push closed MEK with Selumetinib?
This article emphasized the fact that this was the first time that KRAS was used as a biomarker for Target therapy. Very true, but mesenchymal transformation and angiogenesis play a role in almost every cancer.
THE FIGHT IS ON.
(LAST POINT: WE HAVE NOT LEARNED ENOUGH ABOUT HOW TO PREVENT THESE SIDE EFFECTS, WE NEED TO STEP UP!)
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