1.Variants in the PALB2 gene are associated with an increased risk of developing breast cancer [5] and PALB2-deficient cells are sensitive to PARP inhibitors. [4]
PALB2 was recently identified as a susceptibility gene for familial pancreatic cancer
by scientists at the Sol Goldman Pancreatic Cancer Research Center at
Johns Hopkins. This has paved for the way for developing a new gene test
for families where pancreatic cancer occurs in multiple family members.[6] Tests for PALB2 have been developed by Ambry Genetics [7]and Myriad Genetics[8] that are now available through a genetic counselor.
Biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia.[3]wikipedia
2 xia et al: described superbly the role of PALB2
" the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes
with BRCA2 in nuclear foci, promotes its localization and stability in
key nuclear structures (e.g., chromatin and nuclear matrix), and enables
its recombinational repair and checkpoint functions. In addition,
multiple, germline BRCA2 missense mutations identified in breast cancer
patients but of heretofore unknown biological/clinical consequence
appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function.
Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and
ensures its tumor suppression function."
3. And has mentioned hematologic complication is not very far!
" Fanconi anemia is a rare, recessive, chromosomal instability disorder
characterized by growth retardation, congenital malformations,
progressive bone marrow failure, cancer predisposition and cellular
hypersensitivity to DNA cross-linking agents1.
The syndrome is genetically heterogeneous with 12 complementation
groups currently recognized, 11 of which have been attributed to
distinct genes: FANCA (FA-A), FANCB (FA-B), FANCC (FA-C), BRCA2 (FA-D1), FANCD2 (FA-D2), FANCE (FA-E), FANCF (FA-F), FANCG (FA-G), BRIP1 (FA-J), FANCL (FA-L) and FANCM (FA-M)2, 3." Sarah Reid et al....
4. And the devastation does not stop to Fanconi and Breast cancer!
ERKKO et al:
"These results indicate that PALB2 is a breast cancer
susceptibility gene that, in a suitably mutant form, may also contribute
to familial prostate cancer development." in a Finnish population
SIAN JONES ET AL
"the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner
for BRCA2. "
SOME AUTHORS ADD GALLBLADDER,MELANOMA AND GASTRIC CANCERS TO THIS SAD LITANY.
====================================================================
6.RAD51
"In humans, RAD51 is a 339-amino acid protein that plays a major role in homologous recombination
of DNA during double strand break repair. In this process, an ATP
dependent DNA strand exchange takes place in which a template strand
invades base-paired strands of homologous DNA molecules. RAD51 is
involved in the search for homology and strand pairing stages of the
process.
Unlike other proteins involved in DNA metabolism, the RecA/Rad51 family forms a helical nucleoprotein filament on DNA.[2]
This protein can interact with the ssDNA-binding protein RPA, BRCA2, PALB2[3] and RAD52."WIKIPEDIA
RAD 51 KEEPS BAD ASSOCIATIONS, BROADENING THE DANGER!
" RAD51 has been shown to interact with BRE,[12] RAD54B,[13] Ataxia telangiectasia mutated,[14] BRCC3,[12] BARD1,[12] BRCA2,[12][15][16][17][18][19][20][21][6][22][23][24][25] UBE2I,[26][27] Abl gene,[14] BRCA1,[12][24][28][29] ATRX,[13][30] RAD52,[14] DMC1,[31] P53[12][32][33] and Bloom syndrome protein.[34]"WIKIPEDIA
====================================
ON TOP OF ALL THIS
YOU STILL HAVE
- CDH1
- p53 MUTATIONS
- PTEN
OUR WORK IS CUT OUT TO TRAVEL THIS MAZE!
Showing posts with label PARP. Show all posts
Showing posts with label PARP. Show all posts
Friday, November 8, 2013
Friday, April 26, 2013
CONSIDERATIONS IN RECURRENT OVARIAN CANCER TREATMENT:
Nice discussion by
By Edward Tanner, MD1, Deborah K. Armstrong, MD2 | April 15, 2013
In summary, and I hope I dig this right!
That one thing you look at in recurrent Ovarian cancer:
ASSUMING YOUR FIRST TREATMENT WAS PLATINUM BASED, WHICH IS MOST OF THE TIME THE CASE, the disease free interval of more than 6 months (not 12 months) determines whether the disease is platinum sensitive. Because re-treatment should include platinum in those with the disease still sensitive!
The other sensitive notion was the issue of Cytoreduction, according to these authors, Cytoreduction in recurrent disease makes sens only if the Progression free interval was more than 1 year (here "12 months" is needed), and when the lesions could be realistically resected! ("gross resection is achievable")
The discussion on Target therapy was limited to:
1. Adding Avastin to Gemzar +platinum which has shown to increase progression free survival
2. to using PARP inhibitors for those with BRCA Mutation
---------------------------------------------------------------
In other news!
"Similarities Between Ovarian and Basal-Like Breast Cancers:
In a copy number and genomic mutation analysis of all four breast cancer subtypes and ovarian cancer tumor samples, basal-like breast cancer and ovarian cancer were found to be most similar. The authors highlight that the similarities between basal-like breast cancer and serous ovarian cancers indicate that these two difficult-to-treat cancer types may be able to be treated with the same therapies—chemotherapy drugs, anti-angiogenesis agents, and others in development."
No comment was reported about the difference on MUCIN genes!
" For both ovarian and basal-like breast cancer, TP53 was found mutated in 80% of tumors," pointing to the Receptor failure theory developed here!
"Basal-like breast cancers and ovarian cancers had similar rates of mutation and a similar spectrum of mutations. The basal-like tumors had a high frequency of mutations in the ATM, BRCA1, BRCA2, as well as RB1 loss and cyclin E1 amplification—the same mutations identified for ovarian cancers.
About 20% of basal-like breast tumors had a germline or somatic mutation in either BRCA1 or BRCA2. The authors suggest that these BRCA-mutated patients could potentially respond to Poly (ADP-ribose) polymerase (PARP) inhibitors. The analysis also showed various copy number amplifications and deletions that may be therapeutic targets."
For more, go to:
By Anna Azvolinsky, PhD1
----------------------------------------------------------------------------------------------------------------------
AND ALSO READ THIS:
By Edward Tanner, MD1, Deborah K. Armstrong, MD2 | April 15, 2013
In summary, and I hope I dig this right!
That one thing you look at in recurrent Ovarian cancer:
ASSUMING YOUR FIRST TREATMENT WAS PLATINUM BASED, WHICH IS MOST OF THE TIME THE CASE, the disease free interval of more than 6 months (not 12 months) determines whether the disease is platinum sensitive. Because re-treatment should include platinum in those with the disease still sensitive!
The other sensitive notion was the issue of Cytoreduction, according to these authors, Cytoreduction in recurrent disease makes sens only if the Progression free interval was more than 1 year (here "12 months" is needed), and when the lesions could be realistically resected! ("gross resection is achievable")
The discussion on Target therapy was limited to:
1. Adding Avastin to Gemzar +platinum which has shown to increase progression free survival
2. to using PARP inhibitors for those with BRCA Mutation
---------------------------------------------------------------
In other news!
"Similarities Between Ovarian and Basal-Like Breast Cancers:
In a copy number and genomic mutation analysis of all four breast cancer subtypes and ovarian cancer tumor samples, basal-like breast cancer and ovarian cancer were found to be most similar. The authors highlight that the similarities between basal-like breast cancer and serous ovarian cancers indicate that these two difficult-to-treat cancer types may be able to be treated with the same therapies—chemotherapy drugs, anti-angiogenesis agents, and others in development."
No comment was reported about the difference on MUCIN genes!
" For both ovarian and basal-like breast cancer, TP53 was found mutated in 80% of tumors," pointing to the Receptor failure theory developed here!
"Basal-like breast cancers and ovarian cancers had similar rates of mutation and a similar spectrum of mutations. The basal-like tumors had a high frequency of mutations in the ATM, BRCA1, BRCA2, as well as RB1 loss and cyclin E1 amplification—the same mutations identified for ovarian cancers.
About 20% of basal-like breast tumors had a germline or somatic mutation in either BRCA1 or BRCA2. The authors suggest that these BRCA-mutated patients could potentially respond to Poly (ADP-ribose) polymerase (PARP) inhibitors. The analysis also showed various copy number amplifications and deletions that may be therapeutic targets."
For more, go to:
Study Finds Ovarian and Basal-Like/Triple-Negative Breast Cancers Genetically Similar
----------------------------------------------------------------------------------------------------------------------
AND ALSO READ THIS:
ONCOLOGY.
Vol. 27
No. 1
mTOR Inhibitors in the Treatment of Breast Cancer
By Shaveta Vinayak, MD, MS1,
Robert W. Carlson, MD1 |
January 15, 2013
1Department of Medicine, Stanford University School of Medicine, Stanford, California
ABSTRACT: The phosphatidylinositol 3-kinase/mammalian target
of rapamycin (PI3K/mTOR) pathway is commonly dysregulated in breast
cancer. In preclinical studies, hyperactivation of the PI3K pathway has
been linked to resistance to both endocrine therapy and trastuzumab(Drug information on trastuzumab)
(Herceptin). Rapalogs, agents that primarily inhibit mTOR-raptor
complex 1, have been studied in combination with endocrine therapy to
overcome endocrine resistance. Trials of combination endocrine therapy
and rapalogs in metastatic hormone receptor–positive breast cancer have
demonstrated variable results. However, two independent trials have
recently shown that combination everolimus (Afinitor) and tamoxifen(Drug information on tamoxifen) or combination everolimus and exemestane(Drug information on exemestane)
(Aromasin) is more effective than either endocrine agent alone. These
trials selected patients with cancer refractory to endocrine therapy,
which may be important in sensitizing tumors to inhibition of this
pathway. In human epidermal growth factor receptor 2 (HER2)-positive
breast cancer, the early clinical data with combinations of PI3K/mTOR
inhibitors and anti-HER2 therapies are encouraging.
| |
Thursday, January 10, 2013
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!
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!
Sunday, December 2, 2012
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...
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...
Wednesday, November 28, 2012
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.
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.
Subscribe to:
Posts (Atom)