The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression

The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression:

This research project investigates the possibility of combining Etoposide with Histone Deacetylases in the treatment of cancers that display a significant expression of te c-Myc and c-Fos gene.  The drugs proposed for this trial are Etoposide and Histone Deacetylases.

Etoposide was first synthesized in 1966 and is a drug widely used in chemotherapy since 1983 when it obtained  FDA approval. Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme which participates in the unwinding of DNA, hence prevents the rwligation of the DNA strands, and by doing so causes DNA strands to break. This action then  leads to DNA synthesis errors and subsequently to cell death. Etoposide has, however, some reported side effects such as low blood pressure, hair loss, pain or burning at the injection site .

Histone deacetylation has been an effective treatment for various types of cancers. By the removal of acetyl groups from histones, histone deacetylases create a non-permissive chromatin conformation that prevents the transcription of genes that regulate the expression of proteins involved in tumor development such as c-FOS. In addition to histones, histone deacetylases deacetylate a variety of other proteins including transcription factors and other abundant cellular proteins involved  in the regulation of cell growth, differentiation and cell death. Histone Deacetylases are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors worldwide.

The present research project consists in computerized and laboratory testing of the efficacy of combining these two treatments in cases of observed overexpression of both the c-MYC and c-FOS gene.  Although the two drugs already exist and are used in cancer therapy, the interaction of  the two drugs when used in combination needs to be examined. This can be achieved by using a mouse model bearing specified tumors to be done at the University of Texas at El Paso (UTEP). Preliminary testing should be conducted by implanting cancer cells in the skin of mice. The combined treatment should then be applied indiscriminately to mice presenting high expression of c-Myc and c-FOS, and to those with low expression of these genes. The response to the treatment will be monitored to evaluate the efficacy of the treatment in mice with high c-Myc and c-FOS expression as compared to the control group with low c-Myc and low c-FOS expression. In a later phase, testing would be conducted  in cancer patients presenting high expression of c-Myc and c-FOS, especially for patients treated for triple negative breast cancer, but also for ovarian cancer and other types of cancer with an overexpression of c-MYC.

The combination of Etoposide with Histone Deacetylases represents de facto a novelty in cancer treatment, especially in the case of triple negative breast cancer that is until today associated with a worse prognosis than other breast cancer types. It has a characteristic recurrence pattern with the peak risk of recurrence and the majority of deaths occurring in the first 3 and 5 years after the initial treatment, respectively.

IT IS ALL ABOUT THE CYTOKINES!

The discovery of DNA and nuclear material has led to the emphasis on the alteration of Nuclear functions to fight cancer, indeed most of the original chemotherapy drugs had mechanisms of action centered on breaking or somehow impairing DNA.  This focus to a certain extent affected our judgement in the evaluation of certain drugs.  We are now finding out that the strength of certain drug  (and weakness /susceptibility to resistance) is not really due to their main effect on DNA (ie. epigenetic disturbances induced by  Etoposide).  The discovery that BCL-2 has a mechanism of resistance to certain drugs is point in case that nuclear material induced disturbances have significant limitations that occur away from the nucleus (at the Mitochondria).  Anti-proliferative chemotherapies have now shown their limits and scientists have kept this in our panoply of options against cancer.

Scientists have long been fascinated by the laws of nature, these driving forces that drive in certain ways or directions the chains of chemical reactions within the cells.  From Glycogenolysis to the Krebs' cycle, to the cellular pathways, role of enzymes these catalysts of chemical reaction and gene regulators, our focus has been progressively shifting.   The maximal effect of standard chemotherapy having been realized, the shift now has gone to driver Mutations, blocking pathways and modulating reactions etc.   But beyond the mutation, gene alterations and so forth, one thing that make a cancer spread like a wild fire is its stimulation by a growth factor, or its self dependence in achieving survival most of the time at very different levels of energy expenditure!  This role squarely falls into the area of epigenetics which is the critical area of Cytokine production determination.  Now, once produced, Cytokines, to be effective, must connect to their receptors!  This is where the wheels rub the asphalt to speed up the chemical reactions!

One of the mechanisms of increased cytokine production, aside from their gene amplification, is failure at the receptor.  Indeed, when a receptor fails, the normal reaction (law of nature) is to concur the resistance by sending more of the same cytokine.  While this increase could be partially succesful in restoring homeostasis depending on the level of abnormality at the receptor, the relative increase has other side effects due to the non specificity of receptors.  Co-receptors or other receptors susceptible to the same cytokine find themselves super excited and are driving downstream reactions at higher rates.  A SIGNIFICANT PHENOMENON NEEDS TO OCCUR AT THIS POINT, THAT IS THE DESENSITIZATION OF SECONDARY RECEPTORS, A TRAUMATIC PHENOMENON WITH POTENTIALLY NEOPLASTIC CONSEQUENCES   (TO BE CONTINUED)

UPDATE ON TREATMENTS OF PERIPHERAL T CELL LYMPHOMA

3 AGGRESSIVE TYPES:
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1. PTLC- NOS
2. AITL: AngioImmunoblastic
3ALCL (Anaplastic large cell  (ALK +)  6% AND     alk NEGATIVE
CD30 , t(2,5)(p23,q25)
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1 Peripheral T cell lymphoma not otherwise specified
-PET
-Gene Profiling
treat it with EPOCH (CHOEP) or Etoposide based regimen followed by transplant
consider Romidepsin (upfront in Europe)
followed by Gemcitabine, Navelbine (Doxil)

Europeans give ACVBP +/- Romidepsin (Vindesin not available in the US)

refractory disease" FDA has released 3 drugs, their role and position is being evaluated"
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Romidepsin
Pralatrexate
CD30 positive - BRENTUXIMAB VEDOITIN
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2. some T cell lymphoma are clearly Indolent i.e Mycosis Fungoides (MF)
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3. Anaplastic Large cell Lymphoma
ALK negative
for Europeans ACVBP followed by transplant

USA, same paradigm as in PTCL NOS

FOR ALK POSITIVE -- CHOP  ALONE IS THE BEST NO TRANSPLANT (NO ETOPOSIDE NEEDED)   (THE GERMAN STUDY WAS RETROSPECTIVE )
CRIZOTINIB

PRALATREXATE AND ROMIDEPSIN HAVE BEEN USED IN CLINICAL TRIAL
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4. ANGIOIMMUNOBLASTIC

STEROIDS
SOME CLAIM CYCLOSPORINE (PARTICULARLY WHEN HEMOLYTIC ANEMIA)

IN EUROPE CHOP-ROMIDEPSIN

IN USA, GEMZAR
FOR THOSE WITH A COMPONENT OF CD20 POSITIVE, RITUXAN +STEROID

WHATEVER YOU DO, DON'T GIVE ADRIAMYCIN!

Translational Research Project

Research at CRBCM

The CRBCM has determined that Breast Cancer Mortality in African American is excessive.  Of the 6000 African American women who will or have died this year, 3000 could have been saved if leaders paid more attention to this cause.
3 reasons  contribute to this excess mortality
1. Poor rates of screening mammograms in these minority population (or low income populations in general).
2. Late stage of disease at diagnosis
3. POOR HISTOLOGY, high rate of triple negative Breast cancer, which can only be managed by adjuvant and palliative chemotherapy.  Increasingly however, new target treatments are being tried. (ie.PARP and Histone De-acetylator inhibitors).

The success of chemotherapy, the only option readily available to African American women with triple negative Breast cancer is 20-40% at best.  We need further options and further investigation is required.
At CRBCM we believe that the potential contribution of Anti-Kinesin could be even more important, particularly when combined to a Taxane-Cisplatin or related Microtubule disrupting drugs.

The human Genome Project has already determined that the Genome of triple negative Breast Cancer is comparable to that of Ovarian Cancer.This fact re-enforces our choice for Taxane-platinum based combination in this disease.
Another thing we know is that cure happens when the cancer cell is killed.  The killing of cells is induced by Caspase release from cellular mitochondria.  Caspases are lytic proteins to the extent of achieving death by global disruption of sensitive pathways.  To our knowledge one of the determinant inhibitor of Caspase release is the presence of high levels of Bcl-2.  Bcl-2 seems to be more effective in mitigating the effect of drugs acting through the Topoisomerase enzyme (etoposide and Adriamycin)

In a cell such as the cancer cell which naturally intend to divide for growth of the cancer, disruption of Microtubule/microfilament, support scaffolding  for movement of chromosomes during cell division, appears a stronger argument bypassing the Bcl-2 protection for the release of caspases.  In fact, the Mitochondria nearby appear to be located there attached to close-by membranes.  Suffice is to say that significant microtubular or Microfilament  disruption  is not compatible with life.  This is why Taxanes (Erubulin and Ixabepilone) are most likely the most powerful drugs in breast cancer.  It is also why we believe that the right Anti-kinesin could add significantly to the effect of Taxane-platinum combination in triple negative Breast cancer.

Study Methology

1 We will use 50 tissue sample of 4 different cancers (Breast, Colon, lung and liver) for a total of 200 tissue samples.
2.Using Bcl-2 kits, we will detect and quantify Bcl-2 per tissue and per nature of tissue origin.  We can then identify which type of tissue has the highest Bcl-2 at cancerous status.
3.we will expose half of each group of tissue to taxal-Cisplatin ex-vivo. and, using standard kits, will detect and quantify Caspases released.
4. we will expose the other half to a triplet with Taxane-Cisplatin and Antikinesin, and detect and measure quantitatively the level of Caspases released by the tissue
5. Consideration of using Antikinesin alone has been discussed, no one would choose this option given the fact that time and again mono-target therapy have failed to achieve better than 30% because of patient genome heterogeneity.
6. We could also test these tissue response to Etoposide to verify Bcl-2 resistance and therefore appreciate the magnitude of Microtubule disruptions through the Taxane based combinations.

Our conclusions (proof of concept) will relate to:

1. Bcl-2 content by nature of the cancerous tissue.  This would predict sensitivity to tested chemotherapy drugs.
2. Verify sensitivity and specificity of Bcl-2 kits
3. Verify sensitivity and specificity of Caspase kits
4.Verify that Taxane-platinum based chemotherapy is better than Etoposide Ex-vivo.
5.Verify that adding Anti-kinesin improves response to therapy
6. By comparing to Etoposide alone by levels of Bcl-2, verify that Taxane based combination do bypass Bcl-2 protection of Mitochondria
7. If differences are corroborated, we can show that response to therapy can be predicted ex-vivo.

It is evident that such a study provide numerous commercial opportunities when it comes to kit development and Antikinesin  product selections.

Let's work with this Peggy! add any ideas and suggestions
we ask our readers to send their comments. The fight is on for the cure...