LBK1, A CONFUSING MARKER OF CANCER
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In lung cancer, Harvard researchers have pushed us now to request a lengthy list of Markers in order to direct our treatment.  The many options of therapeutic interventions have to be selected more sharply as new Driver mutations are discovered and new Target therapy drugs are made available.  We made a summary of drugs and their relevant Driver Mutations in our previous blog. (KRAS, EGFR, ALK, HER-2, BRAF, ROS-1,RET, MEK-1,NRAS, MET etc. for Driver Mutations.....Medications included Erlotinib, Gefitinib, Herceptin, Lapatinib, Veramufenib, Cabozantinib, Crizotinib etc. - SEE OUR BLOG)

But for a while, 5 Mutations were mostly adopted: KRAS, BRAF, EGFR, ALK and LBK1.
The surprise choice of LBK1 has remained somewhat of a confusion. Because no one knows what to do with the information despite the fact that we know a bit about the gene.  In these days, any Mutation or suppressed gene is suspect and prognosis conclusions are down. Presence of Mutation at LBK1 is considered of poor prognosis.  But wait a second! Let me shake a bit this notion:

Where do we find LBK1 alteration?

In DCIS
and In Polyps
and in Hamartomas ( Peutz Jeggers) : These do not sound like invasive cancers to me!

The DCIS case: Clinicians have maintained that DCIS do not invade, and Lymph node biopsy is generally not performed in case of DCIS.  Malignant transformation occurs here at 1% a year.  So we need additional Mutations for DCIS to adopt a cancerous profile.

In Peuts Jeggers, despite the presence of LBK1 (STK-1), polyps take their time to transform.  There the patient could develop pancreatic cancers for sure, but only after additional mutated genes come to bear! And the likelihood of this is high since a number of known substrates have been recognized to interact with LBK1.

Through Wikipedia:

SUBSTRATES OF LBK1 INCLUDE:

1.   BRSK 1&2 --------Through these substrate, it insure Neuronal Polarity.  And control length of neurons.
                       I should come to cellular polarity in a bit!  But here also comes its power to organize Microtubules and could have implications on resistance vs sensitivity to Taxanes!

2.  MARK 1&2--------This is where it controls Apico-basal cell Polarity, it may be controlling the      popular topic of Flippase, Floppase and Scramblase.

3.  SIK 1,2 : Through this substrate and its co-activator TORC2, LBK1 finds its inhibitory effect on Gluconeogesis.

4. AMPK signal pathways which favor proteins formation and translation while blocking lipogenesis.  Metabolically, it favors Catalysis with generation of ATP while blocking reactions requiring consumption of ATP.  At the cellular membrane the exchange of phosphorylated groups drive GTPase.  Putting LBK1 center to pathways activation.  At the Mitochondrial Membrane this has even more of an impact.

5.  NUAK  1,&2  which regulate Apoptosis through P53.  It is speculated that the overall effect of LBK1 is naturally anti-tumor.  Its alteration stops Apoptosis.

6. In the Embryo, LBK1 has demonstrated a role in Angiogenesis.   MEK or VEGF interaction is assumed.

One speculated that chronic exposure to Insulin like growth factor stimulation, or Estrogenic stimulation or inflammation or chronic mechanical stimulation forces desensitization through SPRADD or other genes altering LBK1 leading to loss of polarity and linear arrangement of cells by dysfunctional adhesion leading to "benign tumorous formations called polyps.  Further alterations happen as abnormal genetic evolution occurs and progresses into a full blown Malignancy.

It is also believed that once malignant transformation happens, LBK1 functions could "amplify" then the transformation favoring cell migration.

Many questions remain to be solved when it comes to LBK1...

FDA Approval for Ixabepilone

Brand name: Ixempra™       (this is old news)

• Approved for breast cancer

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
On October 16, 2007, the U.S. Food and Drug Administration (FDA) approved ixabepilone for injection (Ixempra™, made by Bristol-Myers Squibb) for the following two indications:

• Ixabepilone is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.
• Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

A randomized, multinational, open-label trial of 752 patients with locally advanced or metastatic breast cancer evaluated the efficacy and safety of ixabepilone (40 mg/m2 IV once every three weeks) plus capecitabine compared to therapy with capecitabine alone. Patients had previously received an anthracycline and a taxane, had evidence of disease progression or resistance, or, in the case of the anthracycline, received a minimum required cumulative dose.
Treatment arms were balanced with regards to prior therapies, disease sites, hormone receptor status and HER2 expression. Patients receiving combination therapy had a statistically significant improvement in progression-free survival (PFS), defined as radiologic progression or death from any cause (hazard ratio 0.69, p<0.0001). The median PFS was 5.7 months in the combination arm and 4.1 months in the capecitabine alone arm. Patients in the combination arm also had an increased objective tumor response rate. Survival data for this trial are not yet mature.
Ixabepilone monotherapy was evaluated in a single arm trial of 126 patients with metastatic or locally advanced breast cancer who had previously received an anthracycline, a taxane and capecitabine, and who had disease progression or, in the case of the anthracycline, received a minimum required cumulative dose. Ixabepilone was administered at the same dose and schedule as in the combination trial. The objective response rate based on independent radiologic review was 12.4 percent (95 percent CI: 6.9, 19.9). The objective response rate based on investigator assessments was 18.3 percent (95 percent CI: 11.9, 26.1). The median response duration was 6.0 months (95 percent CI: 5.0, 7.6).
Treatment with ixabepilone caused new or worsening peripheral neuropathy in approximately 65 percent of patients treated. Grade 3 or 4 peripheral neuropathy occurred in 23 percent of patients treated with ixabepilone and capecitabine, with no grade 3 or 4 peripheral neuropathy reported in the capecitabine arm. In the ixabepilone monotherapy trial, 14 percent experienced grade 3 or 4 peripheral neuropathy. Neuropathy was generally reversible to grade 1 or better with cessation of therapy.
Ixabepilone in combination with capecitabine resulted in a 68 percent incidence of grade 3 or 4 neutropenia compared to 11 percent with capecitabine alone. Twelve patients receiving ixabepilone in combination with capecitabine died from complications arising from neutropenia.
The incidence of neutropenia related deaths was higher in patients with baseline moderate or severe hepatic impairment when treated with both ixabepilone and capecitabine. This combination should not be used in patients with moderate or severe hepatic impairment. When used as monotherapy, 54 percent of patients treated with ixabepilone experienced grade 3 or 4 neutropenia.
Other commonly observed toxicities (>20 percent) included anemia, leukopenia, thrombocytopenia, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20 percent in the combination treatment arm: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.
=====================================================from FDA pages.
Ixabepilone,
from Sorangium cellulosum
promote tumor cell death by causing cell arrest in G2/Mphase.
has unique Beta -tubulin binding site
given 16mg/m2  (Vs 40mg Q21D )weekly for 3 weeks every 4weeks. (with Bevacizumab) or in combination with Xeloda as recommended appears to have been used in clinical trial.

TRIPLE NEGATIVE BREAST CANCER, A MELTING POT

The news that the Genome of triple negative breast cancer is similar to ovarian cancer has been good as a starting point. But that is as far as it goes!  Researcher are now scrambling trying to see how to best use this information and there is not one good direction.  In fact if anything, it may have complicated the landscape.
The controversy is compounded by the news that there is not simply a single type of Triple Negative Breast cancer.  This added to the fact that there is not just one type of Ovarian cancer.  So which one is the best approach?  And there are no known good suggestions, because of a lack of comprehensive database for cancer types.  Our cancer knowledge is disconnected.  Someone knows more about this. Someone else knows about that. There are Gaps in the knowledge which prevents us from moving forward.

Some of the facts and knowledge:

1. That the Genome is similar to Ovarian Cancer.
2. That Taxane-Cisplatin works in Ovarian Cancer
3. That PARP may have a role
4. That (low) MEKK1 expression is linked to tumor Response to Cisplatin.
5. That BRAC may impart a poor prognosis to the tumor
6. That Downregulation of STAT1 may play a role in the Oncogenesis of Triple Negative Breast cancer.
7. The almost total lack of Role of P53 alteration
8. Limited role of Kras Mutation
etc.

There are Major Questions of therapeutic importance:

1.Are these cancers MUCINOUS? Is there presence of MUC family members?
If these tumors are mucinous, this is another bad news.  Mucin presence shields against detection by the innate immune system and favors cancer dissemination to go undetected.  Mucin contains molecules that interfere with Glycocalyx, blunting their ability to expose cancer cells to the immune system, and also contain molecules full of Sulfhydryl expressing molecules which have profound interaction with electron based reactions at the membrane and Intracellularly.  These activities are generally protective for the cancer cell.

The Mucinous presence can also be supported by the presence of Galectin 4 (LGALS4)  19q13.3 (Heterozygosity site).   Positive TFF1 of the trefoil factor family which is an Estrogen regulated molecule that could potentially predict some response to hormone manipulation even in triple negative setting.

Amplification of CDX which modulate proliferation, cell adhesion and Apoptosis.  The fact is this CDX could be a driver phenomena as this cancer is known for its ability to have a steady progression.

OTHER Molecules of Importance CDH17, Tetraspanin, MSF1R, E-Cadherin and the Kruppel like factor.

2. These tumors seems to have a survival that is epic, raising the issue of expression of survival pathways MEK, MAP Kinases and C-jun
3. What differentiates Endometrioid Vs other ovarian cancers will play a role in this disease
4. What is the role of target therapy, important in Ovarian cancer, as it relates to Triple negative breast cancer?

We are only just scratching the surface of this problem,
Time to put the puzzle together!

AT A CHECK POINT IN CELL DIVISION 2 MAIN THINGS HAPPEN:

1. DNA is checked for mistakes and corrections are undertaken.2. Chromosome segregation to eventual daughter cells is checked to avoid uneven distribution of the chromosome. 
This last event seems to rely heavily on activity on unattached chinetochores where check point proteins (MAS 1 & 2, UB1 etc.) accumulate and block the APX (Anaphase promoting complex) until the checking is completed and Cyclin B and Securins are ubiquitinated and destroyed to release the check hold and allow mitosis to proceed.

The need for ubiquitination of Cyclin B elevate the role of Proteasome. That is why Antiproteasome appears very important in hematologic conditions where signal transduction and subsequent cyclin activity are the driving forces toward multiplictaion of cancer cells as we stated.

When all this is  going on, the cancer cell is at its weak point. That is why chemotherapy, particularly the Taxanes and the Vinca-alkaloids, is more effective. It not only disturbs the microtubule (inducing the 2nd law), but also breaks the actinic anchors to the cytoskeleton of membranes and cellular matrix causing the "Anoikis" like phenomenon within the cell. Lesion to actin like molecules (anchors) within the central nervous system could lead to neuropathy. As we know it has the side effect of these drugs (proof of concept to follow).

PARP Inhibitors

PARP
Day 2 went very well in Houston
made it on time
in the meantime received positive news from El Paso
can apply for faculty time in clinic at University Medical Center
will be an honor if it gets through'
willing to cover at another Hospital over coming holidays to broaden my share of patients
while veterans physicians take it easy...will use any opportunity to shine.

Now Back to PARP inhibitor, (Poly ADP Ribose Polymerase), they are powerful drugs which follow our first law, they break DNA or cause failure to repair DNA mistakes.  Therefore cause automatic activation of intact P53 to induce automatic cell division Arrest. In other words, they act like Cisplatin and therefore will have a role in Ovarian cancer and by inference, will have a role in basal cell like Breast cancer (or triple negative Breast cancer).   Again, their limitation depend on preservation of P53 and all other molecules of that cascade.  They will also be limited by how fast the cell makes its repair.

Remember the 2nd law is the break of Microtubules/Microfilaments that leads to direct Caspase release, more powerful law.  This implies that a combination of PARP with Taxane (or Ixabepilone or Erubilin)will be the next non platinum combination of significance.

Following this logic, we predict an expanded role to Arsenic trioxyde. But fear of its use resides in its cardiac toxicity. But it acts like a Multikinase inhibitor because it interferes with so many cascades in the signal transduction.  Its limitation could also be that it may not lend itself to combination therapy because of "assumed" risk to the host.

SEARCHING FOR A CANCER CURE

At CRBCM we believe that CPRIT is our necessary path to Victory over Cancer.
We also know we will not get its help this time around, not because we do not deserve the help but frankly because it is distracted.  Science is an objective thing.  It is a race.  You have the right move, the right stuff, you win, no matter where you come from.  It is the Olympics without steroids.

We at CRBCM have understood one thing, in the race for the cure, harnessing the force and laws of nature has an unparalleled advantage.  Forcing a cell to die can be done by telling and convincing it to die. Or blasting it and crossing our fingers and hoping it will die.  Chemotherapy did this mostly the second way but its success was partial.  Chemotherapy only works when it manages to finally talk the language.  Indeed, some chemotherapy manages to reach the syllables of the cellular language of death.

Sorting through the maze of messages, 2 powerful set of syllables come out:

1.  That if it fails to repair broken DNA and therefore does not perform GENE REPAIR, this fact will automatically activate your P53 leading to an automatic stop of the cell into its cycle division.  There is no loophole to this principle unless the P53 is abnormal.   Knowing this is powerful.  Now we understand why Cisplatin (and to some extent Gemcitabine)  is a powerful drug because it disrupts the DNA structure.  We also understand that cells with rapid repair of DNA, will brush it off, literally.

2.with further proof of principle, we believe that there is a second automatic message or syllables.
Destruction of Microfilaments (and therefore secondarily Microtubules in general) during cell division, leads to an automatic release of Caspase from the Mitochondria no matter what (and this is what includes the BCL-2 protection). It is in this law that resides the strength of Taxanes.  Medication that works even in resistant diseases such as Melanoma where Abraxane has a role.  Taxanes' limitations appear to be in the type of microtubules attacked. Medication that attacks Microfilament of the type involved in cell divison, where the Centromere is attached, appears to send a more determinant trigger to Caspase release.  This is where our interest comes in the Anti-kinesin.  We believe and predict that an effective anti-kinesin drug in combination with Taxane and Cisplatin/gemzar based combination, will harness best this law.  They will prove to be effective in cure because they will be effective in both treatment and maintenance settings.  This is also why the combination of Gemzar and Taxol has proven to be the strongest non platinum combination.

Following this principle, we believe now at CRBCM, that target therapy not following the laws of nature will have only 20-30% response rate, meaning effective in only the cells that lack loophole mechanisms.  (this also means because of phenotype heterogeneity, 70-85% of cells have potentially intrinsic loophole to any signal transduction target stimulation or blockage).

Lets keep our eyes on the ball, do not invest in stuff they are throwing at you!  More to come...

Sons of the Sevenless

SONS OF THE SEVENLESS/Hypothesis for cancer Research

As we move forward here at CRBCM, we are increasingy  fond of one line of molecules;
first because of their name, and because we believe that their inhibitors could be the answer to the resistance
to some of the medications already in our armamentarium, namely Avastin,  Imatinib and Herceptin.  We believe that the Sons of The Sevenless which are regulator molecules switching on RAS would break resistance to Tyrosine Kinase resistance.  Sons of the Sevenless, what a name!  But don't you remember they say: "KILL THE SWITCH" AND DARK WILL COME.   THE SWITCH IS THE SONS OF THE SEVENLESS...BASAL CELL CANCER OF THE BREAST, THE CRBCM IS AFTER YOU...SINCE THE SUGGESTION THAT BASAL CELL CANCER OF THE BREAST IS LIKE OVARIAN CANCER BY ITS GENOME.  MARK MY WORD: KILLING THE SONS OF THE SEVENLESS OR KILLING THE SWITCH IS THE KEY TO TREATMENT.

ADDING TAXANE (or better yet an Anti-Kinesin) AFTER KILLING THE SWITCH (SONS OF THE SEVENLESS) WILL TURN ON THE MITOCHONDRIAL CASPASE BY AN INHERENT REFLEX MECHANISM WHICH WILL BYPASS BCL-2.  THAT'S HOW YOU LEAD TO CANCER CURE!

OH BY THE WAY,  ADDING STELAZINE TO AVASTIN MAY JUST DO THE TRICK FOR RECURRENT BRAIN TUMORS TOO. IT IS AN ANTI-CALMODULIN AFTER ALL!

RESEARCH IS ON AT CRBCM.