NEW GENES ARE BEING INCLUDED IN THE CLINICAL THERAPY OF LUNG CANCERS!

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 ?

Activity at CRBCM

Today we have concluded a meeting with DR Zhang and (UTEP) and DR Bryan (Texas Tech) on future projects.  We have discussed our collaborative efforts on several  projects, and discussed to use "gene interference" techniques to affect several genes and see whether we can affect several pathways for the cure of cancer.
Several critical areas:
ie.  Could blocking PMS2 (MLH-1  or MLH1 protein ) increase the efficiency of 5-FU in Colon cancer?
ie. Could activation of ARF amplify MDM2 with increased proteosomal degration of P53 in certain Sarcoma?
ie. Could a genetically engineered AATCC Nucleotide set keep Telomeres busy to increase Apoptosis?
ie. Could genetic instability induced by inactivation of telomerase increase radiation sensitivity and response to certain chemotherapy agents?
ie. Examining the role of RPTPs in Alzheimer dementia
ie. Blocking the Farnesyl to delocalize RAS in lung cancers
ie. Blocking Phospholipase C in PIK3 driven cancers?

The meeting was concluded with a tour of the Laboratory.
Our work is cut out, CRBCM, is still working hard for the cure, no stone will stay unturned!

4 Posters at 1st BIOMED Symposium, El Paso 10/26/2013

Dr.Zhang and Dr.Kankonde, Early Detection of Lung Cancer

 

 Dr. Kankonde, Immunotherapy in Ovarian Cancer

Dr.Kankonde, Decrease of TBI by early use of Butein, a Sirtuin Activator

 

Dr.Kankonde at 1st BIOMED Symposium El Paso, 10/26/2013

 

Dr.Zhang, UTEP, and Peggy Kankonde, Greater East Cancer Center

The MEANING OF THE MDHonors AWARD for CRBCM.

MEANING OF THE MDHonors AWARD for CRBCM.

The CRBCM would like to thank MDHonors for the Research award given to our Coalition and young clinic (Greater East cancer Center of El Paso Texas).  This award will allow to build our institution's primary steps into the research power house we intend to become.  It will formalize in practical terms (working on a tangible research project) some of our collaboration attempts with the University Medical Center in El Paso, and the UTEP (University of Texas in El Paso).  With this award, the CRBCM will continue to march toward the cure day by day, and with confidence and focused vision.   And with this steady progression, victory is certain.  MDHonors revived our hope in the belief that we still have a chance to succeed if we try hard enough!
The cure is within reach, we got to keep on believing that it is reachable, and not get discouraged by politicians and malicious institutions which are distracting our progress toward the cure! 
We can not thank MDHonors enough ; for now let's go to work as we face international scrutiny and the true challenge of a cure for cancers!

And God Bless CRBCM
La lucha continua !

Dr Kankonde.

SOME FACTS ABOUT LUNG CANCER

It is the leading cause of death in many countries,
in the US almost 160,000 deaths per year now,
80% are non small cell cancer of the lung,
some are derived from the Pneumocyte type II (Broncho alveolar),
some from very heavy smoking (small cell characterized by Keratin Pearls and hypercalcemia),
20% localized at diagnosis while more than 50% are already distant at diagnosis, the rest have regional spread.
Smoking provides over 300 Chemicals of which at least 10% are potent carcinogens susceptible of changing genes and receptors on cellular membranes including MUCIN genes.  The Carcinogens create DNA adducts, some will stimulate the AKT pathway directly. Mutation of P53 can happen during MUCIN gene alterations as described.  c-MYC, the gene proliferation amplifier, is often found secondarily activated.

Currently testing is completed for EGFR, ROS-1, ALK, (and in some cases K-RAS in Adenocarcinomas).
(to be continued)

In a retrospective review of Lung cancers , use of Beta blockers may provide survival advantage

*In a retrospective review of Lung cancers , use of Beta blockers may provide survival advantage.

*Ruloxitinib, still the success story in JAK driven diseases.  For JAK driven disease to be seen more in Hematologic malignancy, the receptors for hematologic growth hormones must be stimulated.
COMFORT-1 showed 41.9% of patients on Ruxolitinib had spleen reduction  but in COMFORT-2, only 28% had spleen reduction by week 48.

The JAK inhibitors are now being tried in Pancreatic cancers!

*Obstruction to Cure is not only found in limitation of progress in science, but in man made complications such disparities in funding availability and managed care obstruction to access to known medications!  Cure escapes us for our own doing, in a summary!

*In Breast Cancer, Inhibitors to CD4,6 are proving to be a new approach when given with Letrozole

*In Prostate cancer don't be too eager to use Steroids with enzalutmide.  Steroids may "activate androgen receptors promoting the cancer".   I should confess this point is a bit controversial since that's what we do, stimulate to better kill with chemotherapy (Taxotere-Cabazitaxel).  But the logic may not work for another hormone used for killing.

*In Tivo-1,
they found no survival advantage for TIVOZANIB Vs Sorafenib in patient with Renal Cancer.
Tivozanib is said to be more potent and selective for VEGF receptors!  PFS was superior though with TIVO!

*Check this out!  The global multikinase inhibitor Regorafenib (blocks VEGFR1,KIT,TIE2,PDGFR and RET) got approved for GIST.  patients received 160 mg PO daily x21 Q28. Watch for fatigue hand foot sundrome diarrhea, loss of appetite,HTN,weight loss,rash and fever.  and being an anti-VEGF, bleeding and intestinal perforation of course!  rare cases of Coronary attacks!
*New kid on the block, RAMUCIRUMAB TRIED IN GASTRIC CANCER!

(READ TARGETED THERAPY NEWS)

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 OVARIAN CANCER: (part I)

The notion that there is a particular gene or genes for a specific cancer is attractive, but most of the time only reflects the scientists' tendency to attract the community interest on their findings.  There is nothing wrong with that because their work needs recognition. Recent advances in cure and novel therapeutic approaches have occurred to convince the common of mortals that Researchers are hard at work.  But by now we know that most standard genetic family abnormalities involve only 5-10% of cancers.  That means that no one genetic abnormality stands to justify any specific cancer in-toto. The case of BRCA1 and 2 in Breast cancer.
Breast cancer survivor Women who participated in My talk in El Paso,TX were surprised to learn that 85% of women newly diagnosed with Breast cancer in the US were first in their family.  Everybody was assuming that breast cancer happens because of family predisposition.  This is clearly an underestimation of the heterogeneity of our genetic material.  Don't understand me wrong, there are clear cases of family predispositions, however, we have an approximate 25,000 genes, something and somewhere a significant event can happen anytime.  Also, one should know that there is primary and secondary amplification.  In some cases it is hard to determine which came first (Chicken and egg dilemma ).
Another compounding factor complicating our interpretation in rare cases, is the notion that the cause of cancer can be located in the promoter gene which all of a sudden becomes difficult to methylate or suppress, causing secondary amplification of a gene or of its regulators.
When one wants to look at the genes involved in ovarian cancers, it is good to focus on particular genes (HNF1B) as clearly publicized, but we can't ignore the story of BRCAs, and other family syndromes which harbor Ovarian cancer as a component of the syndrome.  Therapies that are being developed and being effective in Ovarian cancer (Anti MEK) are also pointing to relevant genes.   The story of lung cancer with its ever expanding list of DRIVER MUTATIONS and the advent of MULTIPLEX gene screening is just another proof of the danger of claiming to have discovered THE GENE for a specific cancer!

GENES OF OVARIAN CANCER (to follow)

Molecules and Cancer Cells

Now that we know that the cell does not discriminate about what is the category of this molecule invading me as classified by humans, we are ready to suggest some unconventional combinations of chemotherapy drugs:
Nexavar-Metformin for hepatocarcinoma
anti-MEK- calcium channel blocker for K-ras expressing lung cancer
Antibiotic with impact on splicing molecule with the MTOR
(to be continued)

RANDOM NEWS

*Data released from the CDC 's Office on Smoking and Health were rather sobering.   between 2010 and 2011, the prevalence of Smoking did not drop despite a 58% quitting attempt rate recorded. People just smoke a little less as the proportion of those who reported smoking less than 30 packs per year dropped. In the United states, 19% of the Adult population smoke despite all the warning. This lead to 443,000 or half a million deaths related to smoking related illnesses in the United States alone (latest Jama pg 539).  Of these, approximately 165,000 will die of lung cancer (37%).
Carcinogens in cigarettes, ability to detoxify oneself, and presence of Estrogen receptor Beta in the lung seems to contribute.  Amount, length,and nature  of smoking exposure are recognized variables and influence the type of cancer found.    exposure to Radon, Arsenic, Chromium and others such as Nickel have also been implicated.  Host variations include Cytochrome P450, Glutathione S transferase and DNA repair enzymatic system.  Deficiency of Vitamin A, C beta-carotene, fruit and vegetable consumption have all be recognized to be associated with lung cancer risks.

Kidney, bladder, uterine cervix, head and neck cancers have all been linked to smoking.

*Up to 75% of patients with Bladder Cancer who are of European descent may have rs2294008, making this a significant Biomarker to be understood and targeted.

* A device approved by the FDA can recognize existence of cancer cells at the Margins of surgery to help the surgeon delineate his surgical Margin.  The Margin Probe uses an eletromagnectic recognition system to identify a "signature" of malignancy to tell the presence of Malignant cells.  This device can tell 3 times better reportedly where the cancer tissue ends!

*OFF AGAIN, ON AGAIN, MULTIVITAMIN SUPPLEMENTATION IS GOOD FOR YOU TO REDUCE RISK OF CANCER PER THE PHYSICIAN HEALTH STUDY II DESPITE THE LACK OF SIGNIFICANT DIFFERENCE IN MORTALITY.  THE DIFFERENCE WAS IN NUMBER OF CANCERS.  

PRELIMINARY DISCUSSION ON THE 4TH LAW. THE 4TH LAW IS BEST UNDERSTOOD AS THE SET OF FORCES THAT DRIVE THE CELL FUNCTIONS IN A PARTICULAR ELECTED DIRECTION.

THE 4TH LAW IS BEST UNDERSTOOD AS THE SET OF FORCES THAT DRIVE THE CELL FUNCTIONS IN A PARTICULAR ELECTED DIRECTION.
At molecular level, this is enforced by GENE AMPLIFICATION.  That is if the cell is going toward differentiation, the cell will make cellular processes to direct all the cellular function to that aim.  for specific cancer this equivalent to the notion of DRIVER Mutation.   Cellular functions are not totally random and living things do not stay still!  life is always on the go, and on the go for survival.  And once it has chosen a direction, it direct its functions toward an overall goal which at cellular level is to ensure survival.  The drive, the stamina, the direction is battery powered and purposeful!
In the cell that drive is powered and to ensure that it has direction,  AMPLIFICATION GENES go to work.

One good example of this is what happens with some Viruses.  A number of viruses when the enter the host cell, will incorporate their viral genome into the genome of the host to manage to use the host survival machinery to their advantage.  Insertion in the genome of the host sometimes is not enough to trigger the use of the Viral genome in the host machinery, the Virus has to recruit a "growth factor" most of the time called FACTOR-1 to ensure amplification of its genetic material.  (this is known for HIV infection)

In cancer cells, there are amplification genes toward the completion and survival of the cancerous process.
In lung and thyroid cancers, TTF-1 represent such a gene.  found amplified in about 10 % of tumors.  Scientist have had trouble defining its role.  But they know its AMPLIFICATION is bad news for the host.  It is a driver gene for the cancerous process.   In the cell, there are several levels of GENE AMPLIFICATIONS.

The first level is mission driven.  If the mission is to differentiate, this 4th law push to achieve the mission.
if the mission is to grow a cancer, the cell uses all its resources to make a "perfect cancer."  This means, tolerate error in the DNA multiplication, down-regulate the repair mechanism, down-regulate or mutate the  regulator of P53, MDM2. Amplify VGEF so that the tumor has plenty of good blood vessels.

The second level of amplification is actually originating from the stimulus, the cause of the transformation.  the cause could be a change in Oxygen level, a break of shorten Telomerase tail, Tumor growth factor (FGF-1), Cyclins, or an oncogenic mutation or break of DNA strands.  This will ultimately stimulate receptors with subsequent signal transduction pathways flow that could be amplified by way of  intensity of the signals, but also enzymatic up-regulation and nuclear transcription amplification.   Amplification can be then cancerous based, but also stimuli caused.

the 3rd amplification is what occurs at the DRIVER Mutation due to growth factors or increased catalytic rate from related enzymes.

It is hard to measure cancer driven gene Amplification.  Most of the study keeps taking Metothrexate and its mechanism of Resistance because amplification of Dehydrofolate Reductase is the mechanism of resistance.  every body focus on this enzyme to measure resistance.   But when you look at amplification at this various levels, it is not  hard to see that these measurements are missing the point or are just misleading.

We will discuss the relevant Genes under the section or Rubric "NOMENCLATURE".  Frankly speaking, we have not finished yet the genes for the 3rd law.

We are working hard at CRBCM!

 

Study: Beta-Blockers May Help Lung Cancer Patients Live Longer By Anna Azvolinsky, PhD1 | January 11, 2013 1Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter Lung cancer patients who take beta-adrenergic receptor antagonists (beta-blockers) may survive longer and have a lower rate of tumor spread. This is the result of a retrospective study of 722 non–small-cell lung cancer (NSCLC) patients published in Annals of Oncology. Ball-and-stick model of the beta-blocker propranolol(Drug information on propranolol NSCLC patients who were taking beta-blockers for an independent condition during their radiotherapy cancer treatment had a 22% improved survival compared to patients not taking beta-blockers after adjustment for factors such as age, disease stage, and concurrent chemotherapy. Patients on beta-blockers survived 23.7 months compared to 18.6 months for patients who were not taking the drugs. Beta-blockers target the beta receptors on heart muscles and smooth muscles and are commonly prescribed for hypertension, cardiac arrhythmias, and as secondary prevention after a heart attack. Zhongxing Liao, MD, and Daniel Gomez, MD, both from the department of radiation oncology at the MD Anderson Cancer Center in Houston, and colleagues compared outcomes of those NSCLC patients being treated with radiotherapy as their main line of treatment who were either not taking or regularly taking beta-blockers to treat another unrelated condition. While beta-blockers didn’t influence the locoregional progression-free survival, the 155 patients on beta-blockers at the time of their radiotherapy lung cancer treatment had better distant metastasis-free survival (P < .01) and disease-free survival (P < .01) compared to the 567 patients not taking beta-blockers. When adjusting for other factors including age, performance status, histology, concurrent chemotherapy, total tumor volume, stage of disease, those on beta-blockers did better in terms of distant metastasis-free survival (hazard ratio [HR], 0.67; P = .01), disease-free survival (HR, 0.74; P = .02), and overall survival (HR, 0.78; P = .02). There was no correlation, however, with locoregional progression-free survival (HR, 0.91, P = .63). There is nothing unique about the combination of radiation therapy as a modality and beta-blocker usage, according to Gomez. “It would not be unreasonable to propose that these results may be extrapolated to other modalities, such as chemotherapy or surgery.” This study is the first to show a link between improved survival and beta-blocker usage in lung cancer patients. Similar retrospective results have been shown for breast cancer, including triple-negative breast cancer and melanoma. Previous studies have also shown that beta-blockers may have antitumor activity, including in lung cancer models. One previous retrospective lung cancer study did not show any benefit of beta-blockers on patient outcomes. The authors note that the study did not take into account any other clinical factors other than beta-blocker usage and excluded patients with chronic obstructive pulmonary disease or coronary heart disease, both of which are common among cancer patients. Further studies, including prospective trials are needed to follow up and confirm these results. Weakness of the current study include missing data of other medications the patients may have taken during their cancer, data from only a single institution, and lack of data on beta-blocker usage prior to and post-radiation therapy. How beta-blockers may affect metastasis is not clear but may help to suppress chronic stress conditions that result from stress hormones, which have been shown to facilitate the spread of tumor cells from their primary site of origin. “We hypothesize that the mechanism of this benefit is by blocking the beta-adrenergic signaling pathway,” said Gomez. It has been demonstrated in both tissue culture and animal model experiments that blocking this pathway can affect the spread and growth of tumors. “Future molecular studies will help us to understand if the mechanism that we propose is correct, and thus if beta-blockers are indeed directly affecting the aggressiveness of this malignancy, or if these findings are due to the activation or inhibition of another pathway,” said Gomez.

Attended Mark G Kris lecture on Lung Cancer  (KRIS IS FROM MSKCC)

Now genetic sequencing is important

Prescribe the following

1)  EGFR-------------ERLOTINIB, GEFITINIB
2)  ALK-----------------CRIZOTINIB
3) HER-2--------------HERCEPTIN, LAPATINIB
4) BRAF -------------------VEMURAFENIB
5) ROS-1-----------------CRIZOTINIB  (AGAIN)
6) RET--------------------------VANDETANIB  (CABOZANTINIB)
7)MET------------------------CRIZOTINIB (AGAIN)

NICE THE PRESCRIPTION SPELLING OUT ONLY THE GENE SEQUENCING, AND LET YOUR PHARMACIST DO THE REST.
QUESTION: COULD THESE DRIVER GENE ABNORMALITIES BE THE SAME IN TRIPLE NEGATIVE BREAST CANCER?

Early detection of Lung Cancer

LUNG CANCER EARLY DETECTION:

CRBCM IS SEEKING FUNDING FOR A STUDY TO SEE WHETHER CURRENT MOLECULAR TESTING COULD DETECT EARLY LUNG CANCER IN SELECTED GROUPS OF HEAVY SMOKERS.  WE PLAN TO SELECT 150 HEAVY SMOKERS (HISTORY OF 60 PACK A YEAR).
OBTAIN SEQUENCIAL SERUM LEVELS OF E-CADHERIN, METALLOPROTEINASE, AND TUMOR GROWTH FACTOR BETA (EVERY 3 MONTHS FOR 1 YEAR).  A PET SCAN WILL BE OBTAINED AT DAY 1 AND DAY 365.  SELECTED INDIVIDUALS  WILL BE OBSERVED FOR 3-5 YEARS THERE AFTER WITH YEARLY CHECK OF MARKERS AFTER THE FIRST YEAR.

ALTHOUGH PET FINDINGS ARE CRITICAL FOR OUR EVALUATION, WHAT WE ARE CONCENTRATING ON IS TO SEE WHETHER THESE "TUMOR MARKERS" FOLLOWED SEQUENTIALLY COULD PREDICT LUNG CANCER IN HEAVY SMOKERS.

IT WOULD BE INTERESTING TO SEE THE LEVELS OF THESE MARKERS ON PATIENTS WITH INCIDENTAL POSITIVE PET FINDINGS.  ANOTHER COROLLARY MEASUREMENT WILL SCREEN FOR ANA AND RHEUMATOID FACTOR TO SEE WHETHER COEXISTING AUTOIMMUNE DISEASES AFFECT THE PATTERN OF THESE MARKERS, PARTICULARLY THE TGF.
SHOULD THESE FINDINGS BE SIGNIFICANT, A TRIPLE KIT COULD BE DEVELOPED FOR EARLY DETECTION OF LUNG CANCER.