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...

Apoptosomes

Apoptosomes: engines for caspase activation.

Adams JM, Cory S.

Source

The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3050, Victoria, Australia. adams@wehi.edu.au

Abstract

"Activation of the caspases that initiate apoptosis typically requires cognate scaffold proteins, including CED-4 in Caenorhabditis elegans, Apaf-1 in mammals and Dark in Drosophila. Each scaffold protein oligomerizes procaspases into a complex called the apoptosome, but the regulation and biological roles of the scaffolds differ. Whereas CED-4 is restrained by the Bcl-2 homologue CED-9, Apaf-1 is inhibited by its WD40 repeat region, until it is activated by cytochrome c, derived from damaged mitochondria. Although Dark also has a WD40 region, its activation does not seem to involve cytochrome c. CED-4 is essential for apoptosis in the worm and Dark for many apoptotic responses in the fly, but the Apaf-1/caspase-9 system probably amplifies rather than initiates the mammalian caspase cascade."
 (end of abstract)
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This research further confirms the path of the second law driving the forces down the cascade of events
starting with Microfilament/Microtubule disturbance or destruction.  The author clearly feels that once the
Apaf-1/Caspase-9 system is initiated, it amplifies its action leading to apoptosis.  Mention of the Bcl-2 (or other molecules comparable) is critical because it is the main barrier to full display toward apoptosis.  Last point :the Caspases are also a family of enzymes/protein based structure/meaning the potency to achieve Apoptosis varies.

Apaf-1 is Apoptotic Protease-activating Factor-1, a key factor in the cascade to Apoptosis.  I should also stress that this factor is more concentrated in liver, spleen, kidney and brain. Tissues where primary tumors are the toughest to treat.  Therefore, targeting this enzyme for activation could drive up Apoptotic cascade or cell death.

Of note, people in full inflammatory process with increased TNF have a mitigated result when it comes to Apoptosis because TNF also stimulate NF-kB which has anti-apoptotic trends.  Unless it chooses to go down the path of death-domain signaling way (Fas) or stimulate MAPK pathway which is more pro-apoptotic.   ARE PEOPLE WITH AUTOIMMUNE DISEASE POOR RESPONDERS TO TAXOL BASED CHEMOTHERAPY BECAUSE OF THIS?  SHOULD WE BE TESTING ANA AND LEVEL OF TNF (Tumor Necrosis Factor) TO GAGE RESPONSE TO THERAPY?