Effective Treatment of Psoriasis with Narrow-Band UVB Phototherapy Is Linked to Suppression of the IFN and Th17 Pathways

Emőke Rácz, Errol P Prens, Dorota Kurek, Marius Kant, Dick de Ridder, Sabine Mourits, Ewout M Baerveldt, Zeliha Ozgur, Wilfred F J van IJcken, Jon D Laman, Frank J Staal and Leslie van der Fits

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Table 2. Effect of narrow-band ultraviolet-B (NB-UVB) phototherapy on pathways known to be therapeutic targets in psoriasis, or targets of UVB radiation

Previous table | Figures and tables index

		Molecules affected by NB-UVB within these pathways
Pathway	P-value	Upregulated	Downregulated
Therapeutic target in psoriasis
Glucocorticoid receptor signaling	1.1E−03	PIK3R1, PIK3C2G, HSPA2, BCL2, IL1R2, TGFBR2, TSC22D3, KAT2B, AKT3, NCOR2, ADRB2, UBE2I	IL8, STAT3, STAT1
VDR/RXR activation	4.2E−03	IGFBP5, NCOR2, CST6	DEFB4, SERPINB1, KLK6, HSD17B2
NF-κB signaling	2.3E−02	IL1R2, CSNK2A2, IL18, PIK3R1, PIK3C2G, AKT3, IL1F7	IL1F9
Induced by UV in normal skin
p53 signaling	2.1E−03	KAT2B, TP53INP1, PIK3R1, PIK3C2G, AKT3, CCND1, BCL2	SCO2
p38 MAPK signaling	3.5E−03	IL1R2, TGFBR2, IL18, H3F3B, IL1F7, EEF2K	IL1F9, STAT1
EGF signaling	5.4E−03	CSNK2A2, PIK3R1, PIK3C2G	STAT3, STAT1
IGF-1 signaling	2.4E−02	CSNK2A2, PIK3R1, PIK3C2G, AKT3, IGFBP5, IGFBP7
Proposed as therapeutic target in psoriasis
LXR/RXR activation	2.5E−04	IL1R2, APOE, IL18, IL1F7, NCOR2	IL1F9, LDLR, CCL7
IL-10 signaling	4.2E−03	IL1R2, IL18, IL1F7	IL4R, IL1F9, STAT3
PPAR signaling	1.8E−02	IL1R2, IL18, IL1F7, NCOR2, PDGFC	IL1F9
IL-4 signaling	2.2E−02	PIK3R1, PIK3C2G, AKT3	IL4R, IL13RA1
Other
GM-CSF signaling	1.5E−04	PIK3R1, PIK3C2G, AKT3, CCND1	CSF2RB, LYN, STAT3, STAT1
Acute-phase response signaling	3.2E−04	PIK3R1, SOCS6, IL1F7, IL18, AKT3	C1S, SERPINA3, STAT3, C1R, IL1F9, SOD2, CRABP2, CFB
IFN signaling	6.3E−04		IFIT1, OAS1, IFNGR1, MX1, STAT1
PDGF signaling	2.1E−03	CSNK2A2, PIK3R1, CAV1, PIK3C2G, PDGFC	STAT3, STAT1
JAK/Stat signaling	4.2E−03	PIK3R1, SOCS6, PIK3C2G, AKT3,	STAT3, STAT1
IL-6 signaling	7.2E−03	IL1R2, CSNK2A2, IL18, IL1F7	IL8, IL1F9, STAT3
Complement system	9.5E−03	CD59	C1R, C1S, CFB
LPS/IL-1-mediated inhibition of RXR function	1.9E−02	IL1R2, GSTA3, APOE, ALDH3A2, CAT, HS3ST6, ABCC4	ALDH1A3, PAPSS2, HS3ST3A1
VEGF signaling	1.9E−02	PIK3R1, PIK3C2G, AKT3, BCL2	HIF1A, ACTN1
Wnt/β-catenin signaling	2.2E−02	TGFBR2, CSNK2A2, FRZB, DKK3, SOX10, AKT3, CCND1	SOX9, FZD5
Xenobiotic metabolism signaling	3.2E−02	GSTA3, ALDH3A2, PIK3R1, MAF, CAT, PIK3C2G, HS3ST6, NCOR2,	ALDH1A3, UGT1A9, HS3ST3A1
Fc ∑ RI signaling	3.6E−02	FYN, VAV3, PIK3R1, PIK3C2G, AKT3	LYN
IL-2 signaling	4.3E−02	CSNK2A2, PIK3R1, PIK3C2G, AKT3

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ASPECTS OF TARGET THERAPY IN TRIPLE NEGATIVE BREAST CANCER.

As one goes in deeper into treating Breast cancer with triple negative characteristics, one quickly realize it is imperative to further assess genome and pathway drivers in order to get to effective therapy.  This type of Breast cancer is driven by polygenic stimulators and prognostic factors.  Recent developments has pointed to STAT1 and its relationship with AKT3 and MAP3-K1.  In the article posted here, MAGI3-AKT3 reshuffling is plenty discussed.  One of the challenge is to find an effective AKT3 inhibitor.   The potential inhibitors have been tested in Melanoma where AKT3 pathway is amplified in 70% of cancer cells.  Generally, an amplification of pathways is linked to overexpression of promoter genes and transcription genes.  This is were gene Methylation can help silence these promoters, and can prove an effective way controlling these disease processes. Once again, we believe that an Interfeon and /or Interleukin combined to an mTor (Afinitor), plus or minus a Taxane would be effective in Triple Negative Breast Cancer.

Breast cancer’s many drivers

By Elizabeth Cooney, Broad Communications, June 20th, 2012

• A breast cancer cell, shown in a color-enhanced scanning electron
  micrograph.
  Image courtesy of Anne Weston via Wellcome Images
  

Breast cancer is not a single disease, but a collection of diseases with dozens of different mutations that crop up with varying frequency across different breast cancer subtypes. Deeper exploration of the genetic changes that drive breast cancer is revealing new complexity in the leading cause of cancer death in women worldwide.
In one of the largest breast cancer sequencing efforts to date, scientists from the Broad Institute, the National Institute of Genomic Medicine in Mexico City, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute have discovered surprising alterations in genes that were not previously associated with breast cancer. They report their results in the June 21 issue of Nature, which is publishing a series of papers characterizing the genomic landscape of breast cancer.
One of the team’s new findings, a recurrent fusion of the genes MAGI3 and AKT3 in what is known as a translocation event, was observed in tumors from a rare but aggressive form of breast cancer known as triple-negative breast cancer. This cancer does not respond to conventional hormone therapy because its tumors lack three receptors that fuel most breast cancers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (known as HER2). But the biological pathway that is affected by the MAGI3-AKT3 reshuffling is already the target of experimental drugs.
The other new alteration reported by the team occurred in two transcription factor genes. Recurrent mutations were detected in the gene CBFB and deletions of its partner RUNX1. Cancer-causing rearrangements of these two genes are common in blood cancers, such as acute myeloid leukemia, but their discovery in breast cancer marks the first time they have been seen in a solid cancer.
“These genes wouldn’t top the list of genes you think would be mutated in breast cancer,” said Alfredo Hidalgo Miranda, co-senior author of the paper and head of the cancer genomics laboratory at the National Institute of Genomic Medicine, known by its Spanish acronym INMEGEN. “That’s exactly the point of doing this type of analysis. It gives you the opportunity to find those genes that you never thought would be involved in the breast cancer process.”
The scientists studied two kinds of samples. They sequenced the whole exomes – the tiny fraction of the genome that encodes proteins – of 103 breast cancer tumors and DNA from normal tissue from patients in Mexico and Vietnam. They also sequenced the entire genomes of 22 breast cancer tumors and matched normal tissue.
Their analysis confirmed the presence of previously known mutations, but it also turned up the unsuspected alterations.
“One of the lessons here is the real diversity of mutations in breast cancer. I think it’s clear there are going to be roughly 50 or so different mutated genes in breast cancer,” said Matthew Meyerson, co-senior author of the paper, Broad senior associate member, and professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School. “There’s a big diversity of driver genes in cancer. We don’t understand what all of them are, but larger data sets will enable us to identify them.”
The mutations in CBFB and RUNX1 point to the importance of understanding cell differentiation – how cells become specialized – and transcription factors that regulate that process of cell differentiation in epithelial tissue, which lines the inner and outer surfaces of the body. Further studies are needed to unravel that relationship, the authors concluded.
For the current study, inspecting the novel fusion gene MAGI1-AKT3 more closely showed not only that the translocation can transform normal cells into cancer cells, but also that the protein produced by the gene is insensitive to certain drugs now in clinical trials, yet sensitive to others.
In general, fusion genes are created within the same chromosome or across different chromosomes when parts of one gene join parts of another to become a novel gene that wouldn’t normally exist. Like the CBFB and RUNX1 mutations, translocations are also more common in blood cancers but until now have rarely been detected in solid tumors, especially breast cancer.
This particular MAGI1-AKT3 fusion gene produces a fusion protein that acts in the PI 3-kinase pathway as an oncogene, or a gene that drives cancer, revealing a new target for potential therapy. The kinase pathway controls a multitude of cellular functions. When a gene is mutated in this pathway, the result is uncontrolled cell growth, a hallmark of cancer.
Other gene mutations in this pathway are well-known, but MAGI1-AKT3 is a first.
“This is the first translocation event resulting in an oncogenic fusion protein that has been identified in this pathway,” said Alex Toker, a professor in the department of pathology at Beth Israel Deaconess and Harvard Medical School. “That’s important because this is one of the most frequently mutated pathways in human cancer, especially in women’s cancers such as breast, ovarian, and endometrial cancer.”
The most frequently mutated pathway is also the most studied and, from a pharmaceutical perspective, among the most “druggable.”
In laboratory dishes, tests confirmed that the novel structure of proteins encoded by the fusion gene provided no place for some drugs to bind but offered targets for other drugs.
“There are many additional studies that need to be performed using mouse models of disease that would recapitulate the expression of this protein in the mammary gland, in addition to the mechanism by which this protein promotes the effects associated with malignancy,” Toker said. “These are all experiments that are under way.”
Once the mechanism at work in triple-negative breast cancer is understood through animal models, the next step would be to test chemical compounds to see how effective they might be at targeting cells that harbor this fusion gene’s protein.

Beyond these scientific findings, the study also represents a closer look at the Latino population, thanks to the collaboration between the Broad and INMEGEN forged through the Slim Initiative in Genomic Medicine.
“The Slim Initiative in Genomic Medicine aims to support the discovery of the genetic basis of diseases such as type 2 diabetes mellitus and several types of cancer which have a profound public health impact in Mexico and Latin America,” said Roberto Tapia-Conyer, director general of the Carlos Slim Health Institute. “This novel bi-national scientific collaboration is contributing to put the Latin American genome on the map of the second generation worldwide genome studies.”
INMEGEN scientists had previously built a large breast cancer study and then scientists at both the Broad and INMEGEN exchanged clinical, biological, and computational information.
“From the Mexican point of view, you can say the Latino population has not been extensively characterized using genomic methods,” Hidalgo Miranda said. “This is a significant contribution to the knowledge of the architecture of breast tumors in this particular population.”
The study represented a first opportunity to study the genetic basis of breast cancer in Mexico. Larger studies will be required to determine whether differences in the spectrum of mutations exist between different populations, but this was an important first step toward that goal.
Contributors to the work also include, from the Broad and its Harvard-affiliated hospitals: Shantanu Banerji (co-first author), Kristian Cibulskis (co-first author), Kristin K. Brown (co-first author), Scott L. Carter, Abbie M. Frederick, Michael S. Lawrence, Andrey Y. Sivachenko, Carrie Sougnez, Lihua Zou, Maria L. Cortes, Shouyong Peng, Kristin G. Ardlie, Daniel Auclair, Fujiko Duke, Joshua Francis, Joonil Jung, Robert C. Onofrio, Melissa Parkin, Nam H. Pho, Alex. H. Ramos, Steven E. Schumacher, Nicolas Stransky, Kristin M. Thompson, Jose Baselga, Rameen Beroukhim, Kornelia Polyak, Dennis C. Sgroi, Andrea L. Richardson, Eric S. Lander, Stacey B. Gabriel, Levi A. Garraway, Todd R. Golub, and Gad Getz (co-senior author). From Mexico: Claudia Rangel-Escareno (co-first author), Juan C. Fernandez-Lopez, Veronica Bautista-Pina, Antonio Maffuz-Aziz, Valeria Quintanar-Jurado, Rosa Rebollar-Vega, Sergio Rodriguez-Cuevas, Sandra L. Romero-Cordoba, Laura Uribe-Figueroa, Gerardo Jimenez-Sanchez, and Jorge Melendez-Zajgla.
The research was conducted as part of the Slim Initiative in Genomic Medicine, a project funded by the Carlos Slim Health Institute in Mexico. The work was also supported by grants from the National Institutes of Health and the National Cancer Institute.
About the Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.
About the Carlos Slim Health Institute
The Carlos Slim Health Institute is a non-profit organization created in 2007 by the initiative of Mr. Carlos Slim-Helú with the purpose of generating solutions in order to help solving Mexico’s and Latin America’s main public health problems focusing on the most deprived populations.
The institute seeks to achieve its objectives by fostering alliances with Mexican and foreign public, private and social institutions in order to support the adoption of innovative, sustainable and replicable solutions aimed at improving the health of the population, such as the use of mobile technologies in health care, on-line based distance learning, translating scientific research into applicable tools, etc. http://www.salud.carlosslim.org
About the National Institute of Genomic Medicine
The National Institute of Genomic Medicine (INMEGEN) was founded in 2004 and became the 11th National Institute of Health in Mexico. INMEGEN's mission is to contribute to the healthcare of the Mexican population by developing cutting-edge scientific research and well-trained human resources. The goal is to apply the knowledge of genomic medicine through innovation, state-of-the-art technology, and strategic partnerships, all the while complying with universal ethical principles.
INMEGEN's main research areas focus on principal complex diseases in Mexico, all based on the genomic characterization of the Mexican population. Examples of these areas are genomics of metabolic diseases (diabetes mellitus and obesity), cancer research, infectious and cardiovascular diseases, as well as nutrigenomics and pharmacogenomics.
One of the features of INMEGEN¹s innovative culture is scientific research and development of technology, which leads to goods and services that can then be used to contribute to better health care for the Mexican people in the knowledge-based economy.
www.inmegen.gob.mx
About Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center is a patient care, research and teaching affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.
About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Boston Children’s Hospital as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

Paper(s) cited: 

Banerji S et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature DOI: 10.1038/nature11154

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A network module-based method for identifying cancer prognostic signatures

Guanming Wu^* and Lincoln Stein

• * Corresponding author: Guanming Wu guanmingwu@gmail.com

For all author emails, please log on.

Genome Biology 2012, 13:R112 doi:10.1186/gb-2012-13-12-r112
Published: 10 December 2012

Abstract (provisional)

Discovering robust prognostic gene signatures as biomarkers using genomics data can be challenging. We have developed a simple but efficient method for discovering prognostic biomarkers in cancer gene expression data sets using modules derived from a highly reliable gene functional interaction network. When applied to breast cancer, we discover a novel 31-gene signature associated with patient survival. The signature replicates across five independent gene expression studies, and outperforms 48 published gene signatures. When applied to ovarian cancer, the algorithm identifies a 75-gene signature associated with patient survival. A Cytoscape plugin implementation of the signature discovery method is available at http://wiki.reactome.org/index.php/Reactome_FI_Cytoscape_Plugin.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production. 

=================================================================

At CRBCM we are waiting for the final article.   These types of article shed a light on how we 

can finally identify some of the driver mutation in basal like breast cancer. Will wait to comment as soon as the final article is reviewed.

Fighting cancer with cell phones: Innovation to save lives in Africa By Teo Kermeliotis, for CNN updated 9:00 AM EST, Mon November 26, 2012 |

Fighting cancer with cell phones: Innovation to save lives in Africa

By Teo Kermeliotis, for CNN updated 9:00 AM EST, Mon November 26, 2012 |

• A Canada-backed body is sponsoring health innovators to pursue creative ideas
• The goal is to improve access to care in developing countries
• Grants of $100,000 have been given to 68 projects, 38 of which will be implemented in Africa
• Successful projects will be able to apply for funding of up to $1 million

(CNN) -- Only innovation can reduce illness and poverty in Africa, according to a program that is funding creative approaches to healthcare in developing countries.

More than 50,000 women die each year of cervical cancer in Africa, according to World Health Organization estimates, as more than 80% of the cases are detected in late stages.

In countries such as Tanzania, where nearly 4,500 women die annually from the disease, the problem is exacerbated by an acute shortage of medical experts and a lack of quality screening services, especially in rural areas.

But now a group of Canadian and Tanzanian health innovators have joined forces to apply simple and safe mobile technologies to improve cervical cancer screening and thus potentially reduce mortality rates in the East African country.

The idea is to send teams of two trained non-physician healthcare workers in remote Tanzania to examine women living several hours away from health centers. The nurses, who will be equipped with cervical screening and treatment tools as well as standard smartphones, will take a photograph of the cervix with their phone and send it via SMS to a medical expert in a specialized clinic.

Trained doctors will then be able to review the image immediately and text the diagnosis back to the health worker, as well as give instructions about treatment.

"That's the beauty of it -- for early grade cancers, those will be able to be treated right in the field, right in the rural area," says Dr Karen Yeates, of Queen's University, Ontario, the principal investigator of The Kilimanjaro Cervical Screening Project.

Read: How the cell phone can improve health care

The effectiveness of the idea will be put to the test in the coming months as Yeates was named Thursday amongst the 68 innovators to receive $100,000 Canadian grants to pursue bold concepts for tackling health issues in developing countries.

In total, some $7 million has been awarded to 51 innovators in 18 low and middle-income countries, and to 17 Canadian projects, by Grand Challenges Canada, a group sponsoring breakthrough concepts to improve health in poor parts of the world. Thirty-eight of these projects will be implemented in Africa.

"This is probably the largest pipeline of innovation in global health from the developing world," says Peter Singer, chief executive of Grand Challenges Canada, which is funded by the Canadian government. "It shows that poor countries are very rich in ideas because talent is everywhere, opportunity is not, and what we are trying to do is to bring opportunity to talent to improve health."

Poor countries are very rich in ideas because talent is everywhere, opportunity is not and what we are trying to do is to bring opportunity to talent to improve health.
Peter Singer, Grand Challenges Canada, CEO

Amongst the Africa-based projects is a new trading system in Kenya where researchers will create a barcoded vaccination card that people can redeem for farm seeds and fertilizer as part of efforts to encourage vaccination of children.

Benson Wamalwa, of the University of Nairobi, says the project "would powerfully incentivize parents to seek and adhere to their children's immunization schedule even when hard pressed financially to reach a distant vaccination center. The idea is a practical solution that would significantly boost small farm productivity and incomes for poor households while safeguarding the general health of children in farming villages through up-to-date immunizations."

Read: How 'Afropreneurs' will shape Africa's future

Other programs include restoring native freshwater prawns in Senegal to eat the populations of snails that are responsible for the spreading of the parasitic disease schistosomiasis; paying youth in Uganda to collect and sort garbage and deliver it to a plant for conversion to fertilizer and biogas in order to improve sanitation; and anti-diarrhea kits for children hitching a ride on Coca-Cola's distribution chain to improve the availability of life-saving drugs.

Grand Challenges Canada says it will repeat its Stars in Global Health program every six months, funding hundreds of projects over the coming years. It also plans to work with partners to provide scale-up funding of up to $1 million to those ideas that are proved to be successful so that they can have a bigger impact in a more sustainable way.

Singer says that many of the traditional approaches when it comes to aid have proved to be inadequate. Instead, he argues, fostering innovation and investing in the ideas of the people can be an effective exit strategy from poverty.

"There are only two ways for a country to develop, there's only two sources of wealth in the world," he says. "Either you mine the ground for resources and minerals, if you do that in a non-corrupt manner, or you mine the brains of your citizens for their bold ideas and help them to create social enterprises, to create businesses that can improve the local conditions in a broader scale."

He adds: "I do think that these innovators can help the problems of their community -- in fact, they are the only thing that can."

SCATTERED NEWS

1. Adding Velcade may increase remission rates in AML.
This was suggested in a study at Massachusetts general Hospital.
2. CD25 was a new prognosis Biomarker in Adult B-ALL.
3. Ibrutinib in combination with Rituxan is effective in CLL
420 mg PO daily with weekly 375mg/m2 of Rituxan for 4 weeks
Rituxan was then continued monthly for 6 months
RR of 83% noted.
4. Preliminary suggestions that patients taking Statins may have a reduced risk of Hepatoma.
5 Pazopanib may be no inferior to Sutent as first line therapy in Metastatic renal cell cancer.
6. Axinitib failed to meet primary end point in Metastatic Renal cell cancer.

ETIRINOTECAN PEGOL WAS GRANTED FAST TRACK BY THE FDA FOR METASTATIC BREAST CANCER REFRACTORY TO TAXANE, ANTHRACYCLINES AND XELODA.
This is the same setting indicated for Ixabepilone (Ixempra) and other Microtubule disrupting agents.
E. Pegol has anti topoIsomerase I activity.  reportedly designed using Nectar's polymer conjugate technology.  Call BEACON III to enroll patients.

As a topo-Isomerase inhibitor, I wonder if Bcl-2 status of patients would be critical in interpreting results?
will see if Researcher are looking at this as way to establish refractoriness?

IS T-DM1 THE NEXT BIG THING IN HER-2 POSITIVE BREAST CANCER, METASTATIC SETTING.

A conjugate drug associating Trastuzumab and DM1, a chemotherapy reported to have 500 times the effect of Taxol, was able to swing 6 month benefit of SURVIVAL as compared to a combination of Lapatinib and Xeloda in women with Metastatic HER-2 positive breast cancer.  Improving SURVIVAL is rarely achieved by most current recommended therapy.  This position this drug to be the next big thing in breast cancer responding to this characteristic.  The Oncology community is still waiting on the FDA to approve the drug last I checked.  T-DM-1 is a large molecule and must be engulfed by the cell by Endocytosis increasing delivery of DM-1 intracellularly, people have suggested this is a "smart Bomb" and Genentech had requested to FAST-TRACK the drug.   FDA did not comply, and some are filing petition to push this government institution to move forward!  Until the FDA approves, the drug is not available to the public!

Novel Cancer Hypothesis Suggests Antioxidants Are Harmful, from Medscape

Zosia Chustecka

Jan 11, 2013

• Worst Hematologic Malignancy Treated Without Chemotherapy

Drug & Reference Information

• Chemoprevention Strategies in Head and Neck Cancer
• Grading of Renal Cell Carcinoma
• Head and Neck Cancer - Resection and Neck Dissection

A new hypothesis that focuses on reactive oxygen species (ROS) proposes that antioxidant levels within cancer cells are a problem and are responsible for resistance to treatment.
The theory destroys any reason for taking antioxidative nutritional supplements, because they "more likely cause than prevent cancer," according to Nobel laureate James Watson, PhD, from Cold Spring Harbor Laboratory, New York.
Dr. Watson, who shared the Nobel prize for unraveling the structure of DNA, regards this theory as being "among my most important work since the double helix," notes a press release from his institution, where he has been director since 1968.
The theory was published online January 8 in Open Biology.
Dr. Watson explains that the vast majority of agents used to directly kill cancer cells, including ionizing radiation, most chemotherapeutic agents, and some targeted therapies, work by generating — either directly or indirectly — ROS that block key steps in the cell cycle.
This generation of ROS creates a hypoxic environment in which cancers cells undergo a transformation from epithelial to mesenchymal cells (EMT).
These transformed cells almost inevitably posses very high amounts of antioxidants, which effectively block the effects of anticancer treatments, Dr. Watson notes. Once a cancer becomes resistant to chemotherapy, it usually is equally resistant to ionizing radiation, he points out.
In addition, these transformed EMT cancer cells generate free-floating mesenchymal cells, which have the flexibility and movement that allows them to metastasize to other body locations (brain, liver, lung). "Only when they have moved do most cancers become life-threatening," Dr. Watson notes.
Interestingly, the widely used antidiabetic drug metformin has been shown to preferentially kill mesenchymal stem cells. "In a still much unappreciated article published 3 years ago," metformin added to chemotherapy "induced prolonged remission if not real cures" in mouse models of cancer ( Cancer Res. 2009;69:7507-7511), Dr. Watson writes. He notes that clinical trials are currently looking to see if adding metformin to chemotherapy provides clinical benefits, but adds that diabetics who have been using metformin regularly have a reduced incidence of many cancers.
Resistance to Therapy From Antioxidants in Cancer Cells
Dr. Watson proposes that anticancer therapies work by generating ROS, which cause apoptosis. However, as cancer cells evolve, they produce antioxidant proteins that block this effect, such as glutathione, superoxide dismutase, catalase, and thioredoxin.
The fact that cancer cells largely driven by RAS and Myc are among the most difficult of cancers to treat could be due to their high levels of ROS-destroying antioxidants, Dr. Watson argues. High antioxidative levels might also explain the effective incurability of pancreatic cancer, he adds.
If this theory is correct, then drugs that lower antioxidant levels within cancer cells would be therapeutic. In fact, the ROS-generating agent arsenic trioxide has been shown to reduce levels of glutathione and thioredoxin. Arsenic trioxide is currently being used to treat promyeloblastic leukemia, but this theory suggests that the drug could be useful in many major cancers.
Nutritional Antioxidants Could Be Harmful
One far-reaching implication of this theory is that antioxidants as nutritional supplements, including beta-carotene, vitamins A, C, and E, and selenium, could be harmful in cancer.
For years, such supplements have been widely hyped for cancer prevention and/or treatment, as has encouragement to eat colorful fruit and berries, which contain antioxidants.

 

The time has come to seriously ask whether antioxidant use more likely causes than prevents cancer.

 

However, Dr. Watson warns that recent data strongly hint that much of the untreatability of late-stage cancer might be the result of "its possession of too many antioxidants, [so] the time has come to seriously ask whether antioxidant use more likely causes than prevents cancer."
Many nutritional intervention trials have shown no obvious effectiveness in preventing gastrointestinal cancer or in lengthening mortality, he writes. "In fact, they seem to slightly shorten the lives of those who take them."
Hence, he concludes, "blueberries best be eaten because they taste good, not because their consumption will lead to less cancer."
Very Complex Process
Maurie Markman, MD, national director for medical oncology at the Cancer Treatment Centers of America, who writes the Medscape Markman on Oncology blog, was asked to comment on the theory.
"The importance of the critical relationship between oxidating activity and antioxidants in the normal functioning of cells has been recognized by many investigators, and it is not surprising that this process would be quite relevant in cancer. However, it must be emphasized that this is a very complex process and the balance between these powerful influences at the cellular level is certain to be very carefully controlled. Further, it should be noted that antioxidants are components of our normal diets. Finally, while a provocative concept, it is most unlikely that a simple approach to somehow removing antioxidants from the body will be a useful strategy in cancer management," he explained.
Open Biol. 2013;2:120144. Full text

 

Salivary Gland Biopsy May Diagnose Parkinson's Disease

Fran Lowry

Jan 10, 2013

Editors' Recommendations

• Does Parkinson's Begin in the Gut?
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• Toward a Blood Test for Parkinson's Disease

Drug & Reference Information

• Breast Stereotactic Core Biopsy/Fine Needle Aspiration
• Breast Biopsy With Needle Localization
• Sentinel Lymph Node Biopsy for Squamous Cell Carcinoma

Salivary gland biopsy appears to be a diagnostic test for Parkinson's disease, a new study suggests.
A biopsy of the submandibular gland that shows the presence of the abnormal protein alpha-synuclein is highly indicative of Parkinson's, as distinct from other neurodegenerative disorders that can mimic the disease, said lead study author, Charles Adler, MD, PhD, from the Mayo Clinic Arizona, Scottsdale, Arizona.
"There is currently no diagnostic test for Parkinson's disease in living patients. The only way to make the diagnosis is at autopsy, when you can see an abnormal protein, alpha-synuclein, in certain brain regions," Dr. Adler, a fellow of the American Academy of Neurology, told Medscape Medical News.
Their preliminary findings were released January 10; full results will be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego.
Densest Concentration
Dr. Adler and his team have been working on determining whether there is evidence of alpha-synuclein in other organs of the body so that they could develop a diagnostic test in living patients.

Dr. Charles Adler

"We previously published the fact that the submandibular gland has one of the densest concentrations of alpha-synuclein in an organ outside the brain. When we tested this in an autopsy study of 28 Parkinson's disease patients, we found that all 28 of them had alpha-synuclein in the submandibular gland," he said.
The discovery led the researchers to biopsy the submandibular gland in living patients with Parkinson's disease to see whether this protein was present. If it was, then the biopsy could potentially be used as a diagnostic test, they reasoned.
The current study involved 11 patients, average age, 67.8 years (range, 61 to 76 years), with a mean duration of Parkinson's disease of 10.4 years (range, 6 to 14 years). All patients were responsive to dopaminergic medication and did not have dementia or any known salivary gland disorders.
The researchers used local anesthesia to perform core needle biopsies of 1 submandibular gland percutaneously using 18- or 16-gauge needles. They extracted up to 5 needle samples 240 to 535 μm thick, as well as samples from 2 to 5 minor salivary glands. The biopsies necessitated 1 to 3 stitches.
The patients tolerated the biopsies very well, Dr. Adler said. Three patients had 1 adverse event each, including a swollen cheek, a sore throat, and excess fluid that was expelled from the needle biopsy site after a sneeze.
Nine of the 11 patients showed evidence of alpha-synuclein in their salivary gland biopsy specimens.
"This really was a feasibility study, and it was important to do this in people who we felt had a higher certainty of having Parkinson's disease. They had symptoms for a long time and they were responsive to medication," Dr. Adler said.
Next Steps
The next step is to perform biopsy in patients who have had Parkinson's disease symptoms for a shorter duration.
"In people with more recent onset of disease, the accuracy of our clinical diagnosis is not as high. A lot of people who look like they have Parkinson's disease early on really don't have it, so we'd like to see if this biopsy test would be able to prove the presence of PD in earlier-onset, shorter-duration patients," he said.
Making a more accurate diagnosis in living individuals may improve the outcome of clinical trials, as well as the outcome of invasive procedures that are currently done for people with Parkinson's disease, he added.
"Doing the biopsy and finding the abnormal protein would tell us that we are in fact treating Parkinson's disease because before, we wouldn't be quite sure. There are a number of different studies, including data from our own which we haven't published yet, showing that the accuracy of the clinical diagnosis ranges anywhere from about 50% when somebody first presents with what looks like Parkinson's disease, up to about 80 to 90% for somebody who has had the disease for 5 or 10 years," Dr. Adler said.
"So, even at 10 years, accuracy is still not 100% for what we see clinically because there are many different neurodegenerative diseases that look like Parkinson's disease."
This study was funded by the Michael J. Fox Foundation for Parkinson's Research. Dr. Adler has disclosed no relevant financial relationships.
American Academy of Neurology 65th Annual Meeting. Abstract 1777. Released January 10, 2013.

 ==================================================================

Interesting!  from Medscape!

INTERFERON AND AFINITOR, A POTENTIAL COMBINATION FOR TRIPPLE NEGATIVE BREAST CANCER.

In a recent report about the genome of triple Negative Breast Cancer, researchers reported that there are 3 genes discovered at greater the 10% in this disease.  One of which was STAT1.  In a discussion with Reporters, DR Baumback-Reardon reported "one of the genes down regulated in the Kenyan tumors (with triple negative Breast cancers), STAT1 , is especially noteworthy in that it is has tumor suppression and immune regulating activity".   Interferon has these 2 abilities combined just perfectly.
The Mammallian Target of Rapamycin (mTor) which affect Mitochondrial function are known to affect STAT1.  It would be of Interest to see if this combination of Interferon alpha would be useful to stop Breast Cancer of triple negative nature in its track.
Adding Afinitor to exametestane has already proven a rescue option in patient AI refractory disease
but science is pushing us to believe Afinitor has a long way helping in other areas!

IS STAT1 EXPRESSION A DRIVER GENOME VARIABLE IN TRIPLE NEGATIVE BREAST CANCER?  

IT IS ALSO KNOWN THAT MTOR INHIBITOR HAVE ACTIVITY IN BRAC-1 CELL TUMORS WHICH IS 85% OF TRIPLE NEGATIVE  BREAST CANCER  IN SOME REPORTS

FDA APPROVES MANY DRUGS

1.CABOZANTINIB, A AMULTIKINASE INHIBITOR,
with action on RET, VEGFR2, RET,
It gave a Progression free survival of 11months Vs 4 months for placebo
Indication: Metastatic Medullary Thyroid cancer
the study was not powered to show survival benefit.

THIS THE SAME DRUG WHICH OF INTEREST IN OVARIAN CANCER (AFLIBERCEPT,ANOTHER DRUG OF INTEREST,  HAS BEEN COMBINED TO TAXOTERE IN THIS DISEASE )

2.Earlier Use of Abiraterone approved
in April 2011, this drug was approved fur use after failure of Taxotere and prednisone
(continue Prednisone while on Abiraterone)
Now the drug can be used before Docetaxel.
side effect include fatigue joint pain and swelling, hot flush, diarrhea, vomiting high blood pressure cough bruising and Urinary tract infection.

3.Other news
Treatment Sequencing in Metastatic prostate cancer
1. Local therapy for early disease (Radiation Vs Surgery)
2. Androgen Deprivation +/-  RT (with pelvic disease)
3. consider Sipuleucel-T, an autologous cellular immunotherapy for treatement of asymptomatic or minimally symptomatic metastatic disease (3 doses Q2weeks)
4. or go to Abiraterone (Apharadin, Enzalutamide)
5. Docetaxel and prednisone
6. Cabazitaxel

with bone involvement demonstrated Zometa or Denosumab indicated.

4. OTHER NEWS.
clinical importance
Circulating Breast cancer cells of <5 cells by 7.5 cc of blood   Vs  >5 cells,  progression free survival
21,9 months Vs 10.9 months.  CTC (circulating tumor cells) is held by some as the best predictor of recurrence.
This technology is being pushed in Melanoma, here surrogate for cell counts are MART-1, MAGE-A3 and GalNAC-T.  At 57 months follow-up, 15 of 32 patients with 2 or more markers at diagnosis had recurrent disease! That is 47%.


From Oncology/Biotech News.

"NEVER MIND DRUG RESISTANCE" IN CLINICAL ONCOLOGY.

As we are advancing toward the cure, one of the thing that should change is our general attitude in Oncology clinical practice and clinic trial build up, is to stop dismissing drug resistance as an important component or criteria to include in our drug selection.  With that dismissal comes however a significant effect on outcome.
It is known that addressing mechanisms of resistance to drug improves outcome.  This is entering now clinical practice when it comes down to use of Tamoxifen and related pathway modulators, and the P450 Isoforms CYP2.

In each individual cancer patient there Resistance mechanism due to the host, and those due strictly to the cancer cells.  The complexity of this resistance lead to its dismissal. We kind of walk away from this hoping it is not coming to haunt us!    Unfortunately it does.

Variable Host factors include rate of absorption of the intended drug, rapid metabolism, excretion, poor tolerance and ability to deliver at the site of the intended action.

Variable Cancer cellular Factors include blood vessel variations, loss of surface receptors or transporters, presence of MDR (multiple drug resistance factor), gene heterogeneity/heterozygosity , and ability to compartmentalize the drug once absorbed by simple diffusion, active transport or Endocytosis.

There are Variable factors inherent to the drug itself, its molecular size (immunotoxin requires Endocytosis), liposolubility and hydrosolubility.

The worse of the resistance mechanism  is of course the MDR that we try very much to forget.  Yet we know something about it.  We know it works with ATP interaction, we know it is a Technetium Sestamibi  substrate and can be visualized radiologically, we know there are various kinds.  Some kinds can only handle neutral electrically charged molecules, some more effective in neutralizing cationic or anionic molecules.  And of course we know what drug behave electrically opposite to the MDR tendency.  Suffice is to say that knowing more about the mechanism of resistance we face in individual cancer provide an opportunity to increase outcome.  The future will require this level of discernment.

TRAVEL: Come spend 36 Hours in El Paso, Texas!

Travel:
I COULD NOT RESIST.  THIS IS THE BEST ARTICLE EVER ON EL PASO!

36 Hours in El Paso, Tex.

Mark Holm for The New York Times

Clockwise from top left: Taking in the view from Scenic Drive, boots on El Paso Street, Lotus dance club, the Plaza Theater, the Hoppy Monk and Ardovino’s Desert Crossing. More Photos »

By IZA WOJCIECHOWSKA

Published: December 27, 2012

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El Paso, Tex.

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Friday

4 p.m.
1. WINE COUNTRY

Though El Paso’s summers, with days that often reach into the 100s, may seem an unforgiving setting for grape-growing, it turns out that zinfandels take quite nicely to the sun. Stop by Zin Valle Vineyards (7315 Canutillo La Union Road; 915-877-4544; zinvalle.com) or the neighboring La Viña Winery (4201 South Highway 28; 575-882-7632; lavinawinery.com) for generous wine tastings (free at Zin Valle or $5 at La Viña). Both sit along the historic Don Juan de Oñate Trail, a section of El Camino Real, which marks the route that Oñate, the explorer and conquistador, forged in 1598 to settle north of the Rio Grande. A drive down this road reveals majestic pecan groves and vast fields of cotton, chile peppers and corn.

7 p.m.
2. EAT LOCAL

With Juárez right across the highway, it’s a no-brainer that El Paso has always been a prime spot for Mexican food. And though enchiladas and tortas still prevail, the past few years have begun to see a locavore, foodie culture spread through the city. And why not? With plenty of undeveloped land still surrounding El Paso, there’s room to cultivate nearly everything. Tom’s Folk Cafe (204 Boston Avenue; 915-500-5573; tomsfolkcafe.com) epitomizes the new El Paso dining scene, and the tiny restaurant would feel at home in Brooklyn with its local meat, veggies and breads, wine-bottle candlesticks and nouveau Southern food. After an order of hush puppies stuffed with pulled pork ($14), try an oversized burger with Brie, bacon and blueberry jam ($10.50) or pan-seared snapper with crawfish ragout ($20).

9 p.m.
3. INDIE SCENE

New music venues are part of El Paso’s night-life scene, and with the Coachella music festival to the west and Austin City Limits festival to the east, El Paso could be on its way to becoming a hot spot on indie bands’ tours. The Lowbrow Palace (111 Robinson Avenue; thelowbrowpalace.com) caters to the college crowd and regularly features local bands as well as touring acts. Tricky Falls (209 South El Paso Street; 915-351-9938; trickyfalls.com) is a brand-new music space in a gorgeous historic building; right above it is Bowie Feathers (209 South El Paso Street; 915-351-9909), a bar and hipster haven with black leather booths and funky wall art that also hosts musicians.

11:30 p.m.
4. BAR-HOPPING

Since Mexico’s drug war pushed night life over the border from Juárez to El Paso, new bars are packed with thirsty customers. Choose among drink specials at Hope and Anchor (4012 North Mesa Street; 915-533-8010; hopeandanchorelpaso.com) on the large back patio strung with lights and paper lanterns, or if beer is your thing, go down the street to the Hoppy Monk (4141 North Mesa Street; 915-307-3263; thehoppymonk.com) and try one of the 70 or so craft brews on tap.

Saturday

9 a.m.
5. FARMERS’ MORNING

Drive into the desert for brunch at Ardovino’s Desert Crossing (1 Ardovino Drive; 575-589-0653; ardovinos.com) — and if it’s warm enough (which it often is, even in winter), hang out on the patio beneath the big, blue sky. A recent brunch included a prickly pear mimosa ($5.50), caramelized grapefruit ($2.50) and Jackpot Waffle topped with chicken, bacon and sautéed apples ($12). Leave room for red-wine-infused ice cream with chocolate cake ($9) and watch the train rumble by at the foot of Mount Cristo Rey. If you’re here between May and October, check out the adjacent Farmers’ Market, which features local produce and artisan crafts with local flair. Pick up ocotillo-flower soap ($4.50), a jar of raspberry chipotle jam ($8), or some edible desert delicacies, like cactus fruit or yucca.

11 a.m.
6. DESERT TRAILS

El Paso’s beauty stems from the inescapable mountains that surround the city. Head to the Franklin Mountains State Park ($5; on McKelligon Canyon Road; 915-566-6441; tpwd.state.tx.us/state-parks/franklin-mountains) to hike desert mountain trails replete with cactuses, agaves and lizards. Explore McKelligon Canyon if you enter the park on the east side of the city, or begin a trail from the Transmountain Road entrance on the west.

1 p.m.
7. ARTS AND CULTURE

A serious push over the last few years to revitalize the downtown is finally bearing fruit. Renovated historic buildings are getting their due, and a spate of fresh establishments is breathing new life into classic El Paso haunts. Visit the free El Paso Museum of Art (1 Arts Festival Plaza; 915-532-1707; elpasoartmuseum.org) for its collection of Southwestern and local artwork, right next to the Plaza Theater (125 Pioneer Plaza; 915-534-0600; theplazatheatre.org). The pride of El Paso when it opened in 1930, the Plaza experienced a decline in the ’50s and a near-demolition in the ’80s, but the theater has recently made a triumphant return as a beautiful, colorful setting for Broadway shows and the El Paso Symphony Orchestra. For a taste of (more lowbrow) local flavor, wander down El Paso Street, which is lined with pawn shops and Mexican stores full of cheap clothes, cowboy boots and oddities. Pancho Villa’s dismembered trigger finger has a going rate of $9,500.

5 p.m.
8. COCKTAIL HOUR

Historic El Paso lurks in its old, classy bars. Have a mojito beneath the rotunda of vintage Tiffany glass at the Camino Real Hotel’s Dome Bar (101 South El Paso Street; 915-534-3000; caminorealelpaso.com/dining), or settle in with a top-shelf drink or cigar at the luxurious, nearly 100-year-old Café Central (109 North Oregon Street; 915-545-2233; cafecentral.com).

8 p.m.
9. SHARING TAPAS

Across the street from an old locomotive on display in the downtown entertainment district is a cobbled block of dimly lighted restaurants. Tabla (115 Durango Street; 915-533-8935; tabla-ep.com) leaves little to be desired with its modern décor, a rotation of custom-infused liquors and an extensive menu of tapas. Its mantra is “share,” and after sharing pork confit with goat cheese polenta ($12), grilled asparagus with Serrano ham and salsa verde ($8), and huge pieces of bruschetta loaded with smoked salmon ($10), you’ll also be sharing exclamations of delight.

11 p.m.
10. DANCE, DANCE, DANCE

Locals used to flock across the border on weekends to fill upscale Mexican nightclubs, but the clubbing scene has lately shifted to downtown El Paso. The brand-new Lotus (201 North Stanton Street; 915-503-2335; lotusep.com) is a sleek and ultramodern club with three floors, two separate D.J.’s and a huge Buddha sculpture presiding over the dance floor. The nearby Garden (511 Western Street; 915-544-4400; thegardenep.com) has a daytime dining patio that is transformed into an outdoor club on weekends.

Sunday

10:30 a.m.
11. BORDER-TOWN BRUNCH

Pile green chiles, chorizo, avocado and chipotle onto eggs and serve with a side of black beans, and you have a true Southwestern breakfast. A surprisingly chic spot in a nondescript strip mall, Ripe Eatery (910 East Redd Road; 915-584-7473; ripeeatery.com) stands out for its Southwest Scramble ($9) and Brisket Ranchero Eggs Benedict ($11). Wash it down with a cold Chelada (beer, Bloody Mary mix and lime, $4.75) and then stop by Valentine’s Bakery (6415 North Mesa Street; 915-585-8720) for an assortment of delicious Mexican pastries — and at 80 cents apiece, you might as well try all of them.

1 p.m.
12. 2 COUNTRIES, 3 STATES

Take a ride along Scenic Drive, which winds through the mountains with views of the city and deposits you near the Wyler Aerial Tramway (1700 McKinley Avenue; 915-566-6622; tpwd.state.tx.us/state-parks/wyler-aerial-tramway). This is one of the only public trams in Texas, and the four-minute ride to the peak of the mountain ($7) ends in panoramic views of the convergence of two countries and three states (Texas, New Mexico and Chihuahua, Mexico).

IF YOU GO

Built 100 years ago as the ultimate in luxury, the Camino Real Hotel (101 South El Paso Street; 915-534-3000; caminorealelpaso.com), with rooms from $69, still preserves much of its prestige and history in the original, vintage lobby bedecked with chandeliers and ornate golden molding. During the Mexican Revolution, guests would gather on the hotel’s rooftop to watch battles play out below.

The DoubleTree Hotel (600 North El Paso Street; 915-532-8733; doubletreeelpasohotel.com) with rates starting at $84, is a new addition to El Paso’s downtown skyline, and its rooms and public terrace provide wonderful views of the city.

I COULD NOT RESIST.  THIS IS THE BEST ARTICLE EVER ON EL PASO!

INFLUENZA? HOW MUCH? READ THIS ALERT FROM A HOSPITAL PRESIDENT!

INFLUENZA?  HOW MUCH?
READ THIS ALERT FROM A HOSPITAL PRESIDENT!

                                                                                                                                                           "JAN 10, 2013

The surge of influenza is affecting our bed status. I need your help ensuring our ill patients can get cared for appropriately.

Please:

1) Discharge as soon as possible any patients able to receive ongoing care at home or a skilled nursing facility.

2) Take patients off cardiac monitoring as soon as you recognize it is no longer needed.

Thank you."

Cancer Prevention and Research Institute of Texas and CPRIT Foundation

in Texas.CPRIT

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As I am sure you are aware, recent media reports have raised issues  and concerns about the operations of the Cancer Prevention and  Research Institute (CPRIT) and its relationship to the CPRIT Foundation.   As those stories have come to light, Texas legislators and members  of the media have asked us to release the names of our donors and the amounts of their contributions.  Thus far, we have honored the  Donors’ Bill of Rights we adopted to protect your privacy and  confidentiality. However, the Executive Director of the Institute has received the  same requests and has now formally asked that we provide him that information.  We feel it is important to comply.  This list of all  donors’ names and contributions will be sent to state leadership,  legislators, and the media later this week. Under the circumstances, we believe it is in the best interests of CPRIT to release these names.  It is important to avoid even the appearance of impropriety and to protect the integrity of the institute. We wanted you to know in advance that we are taking this action.   As a reminder, if you were a sponsor of one of our events or the annual conference you have already been listed publicly (signage, programs,   etc.) as a donor to the Foundation. Thank you for your contributions in support of the CPRIT Foundation.  Through your generosity, we are able to provide crucial  financial assistance for the groundbreaking, lifesaving work in all areas  of cancer prevention and research being done through the Cancer  Prevention and Research Institute of Texas and we look forward to   continuing this important work in the future. Please feel free to contact me if you have any questions or concerns. Jennifer Stevens Executive Director CPRIT Foundation

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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!

Researchers from the Memorial Sloan K. have confirmed the principle that reading phenomena at the cell membrane you could predict recurrence and prognosis of cancer. They looked at patients with stage I lung cancer (earliest stage) and could predict recurrence based on concentration of membrane receptors to IL 12 and IL7.  We know that increased Growth factor Receptor promote cancer cell in an autocrine fashion.  This finding seems to reinforce this knowledge.  We have discussed the GLYCOCALYX, activity of the Flipase/Flopase and other changes that may attract the Macrophage.  We also have shown that through the Caspase 8, membrane occurring phenomena could induce Apoptosis without nuclear involvement.
Focusing on membrane activity take you also to the Calmodulin and initiation of signal pathways.  All is happening at the membrane, and a focus at these changes is warranted!

TAXOTERE-CISPLATIN SUPERIOR TO TAXOTERE-XELODA IN TRIPLE NEGATIVE BREAST CANCER

In a recent article published in the Annals of Oncology, Researcher published that Taxotere Cisplatin was a better combination for initial therapy in Metastatic triple negative breast cancer:
"Results:

• The median follow-up was 24 months. ORR was higher in the TP group than in the TX group (63.0% versus 15.4%, P = 0.001).
• PFS was more than doubled (10.9 months versus 4.8 months, P < 0.001) and median OS was also greatly improved (32.8 months versus 21.5 months, P = 0.027).
• Toxic effects were not different except G3/4 vomiting and G2/3 hand-foot syndrome.

Read more: http://www.mdlinx.com/oncology/news-article.cfm/4317563"

These results corroborate or tend to support many facts:

1. That triple negative Breast cancer genome was closer to ovarian cancer, a disease in which   Taxol -Carboplatin is still standard of care particularly in metastatic setting.

2.  That Cisplatin alteration of DNA is more likely to induce P53 cell cycle arrest. (1st law)

3.  That adding Taxotere and its disruption of Macrotubules recruits effectively the 2nd law.   This lead to a doubling  of PROGRESSION FREE SURVIVAL.

Again it would be of interest to see what an Anti-kinesin  (anti-Actin) or Velcade addition would mean in a  clinical trial.   Most molecules involved in programmed cell death such as Cytochrome C are attached to membrane within the organel where they reside.  Disrupting that anchor would most likely boost Apoptosis.  Without further determining the nature of that Anchor, we know that the cytoskeleton is most likely Actinic in nature.  Disruption of the the Cytoskeleton could induced Anoikis, and freedom of molecules attached to membranes leading to major disruption including that of signal pathways.

Velcade main additional effect is disruption of DNA replication restarting after P53 arrest by its affect anti-proteasomic.  Protein restarting the replication are generally ubiquitinated making the front and center to proteasome role!  The issue really remains the determination of how much of a Driver this pathway is in solid tumor.  This determination is one of the major challenge oncologist face today!