Cancer: testing, curing and prevention

I don't completely understand but this sounds like it is new and important (years from now, probably):

"... In order for DNA to replicate, it has to unwind its double helix, which is formed out of two strands of amino acids coiled together. This unwinding is done by a replication fork whereby the two strands are separated. These strands, which form two branching prongs of the replication fork, serves as a template for production of a new complementary strand.

That task is fairly straightforward on what is known as the "leading" of the two strands. The replication fork moves along from the so-called 3' (three prime) end to the 5' (five prime) end, and DNA polymerase synthesizes a 5' to 3' complementary strand.

But because the two strands are anti-parallel, meaning they are oriented in opposite directions, the work of DNA polymerase, which can only work in the 5' to 3' direction, is more difficult on the so-called lagging strand. This strand needs to be replicated in pieces, which are known as Okazaki fragments, located near the replication fork. These fragments include a "primer," a strand of RNA that serves as a starting point for DNA synthesis.

This is where FEN1 comes in—it removes that RNA primer on the 5' flap, which occurs every 100 base pairs or so on the lagging strand, said Tainer. It's an enormous job that has to be done rapidly and accurately in order to glue the ends of replicated DNA on the lagging strand together to eventually provide an intact chromosome. "To replicate one DNA double helix in one cell you have to cut off a 5' flap so that you don't have one base pair too many or one base pair too few, and you have to do this accurately with 50 million Okazaki primers in each cell cycle," Tainer said. "It has always been a mystery as to how FEN1 can precisely cut this flap so efficiently and so rapidly. It's an amazing, efficient molecular machine for precisely cutting DNA."

To determine what FEN1 looked like in action, Arvai led the difficult but ultimately successful effort to grow crystals of the human FEN1 protein bound to DNA. The team then used X-ray crystallography to determine the atomic structure of the complex. Using Lawrence Berkeley National Laboratory's Advanced Light Source beamline, called SIBYLS, the scientists solved three different crystal structures.

The end result was a highly detailed and accurate model showing the structures of DNA before and after being cut by FEN1.

Earlier crystal structures suggested that FEN1 first grabs onto the flap of the 5' single stranded DNA, slides down to the joint where DNA is duplicated, and cuts and patches the primer there. But the new study found that, in fact, FEN1 binds, bends, frays, and then cuts the DNA.

"It binds duplex DNA, bends it into a single-stranded DNA right at the flap, flips out two base pairs, and cuts between them," said Tainer. "This gives FEN1 very precise control—a sophistication we had not expected."

Clues to cancer control

Researchers know that mutations in FEN1 can predispose humans to cancer growth because errors in flap removal can create unstable DNA that promotes cell growth and division. And studies in mice have shown that when one of two inherited FEN1 genes are knocked out, the mice are predisposed to cancer development if their DNA is damaged.

While other DNA repair systems can help compensate for FEN1 mistakes, or for missing FEN1 activity, "you need a lot of FEN1 for DNA repair and replication to work properly," Tainer said.

This suggests that, in tumors already missing one set of repair proteins, selectively inhibiting the function of FEN1 in rapidly replicating cells may prove to be an effective anti-cancer therapy. "The Achilles heel of cancer cells is defective DNA repair pathways," said Tainer, "because that makes them more sensitive to traditional therapies, such as chemotherapy and radiation. If cancer can't repair the damage these therapies do to tumors, they will die."

This is the paradox of DNA repair: while a defect in DNA repair can cause cancer, knocking out a number of backup repair systems may make tumors vulnerable to anti-cancer therapies.

"My hope is that our finding of how FEN1 works mechanistically might provide a foundation for a next-generation cancer drug," said Tainer. "We need to cut as many lifelines as possible in cancer cells in order to provide an effective treatment." ..."

FROM: http://www.therapeuticsdaily.com/ne...e=774976&contentType=newsarchive&channelID=26

 

Log in or Sign up to hide all adverts.

At the Cyberknife Institute of Mercy Hospital, we are practicing the most advanced, yet safe, techniques for the treatment of intracranial tumors and vascular lesions. During a CyberKnife treatment, imaging cameras determine the actual location of the lesion. Each time the robotic arm repositions to deliver another fraction of the ablative dose, the CyberKnife computer recalculates the true position of the targeted area. The result is unsurpassed, submillimeter accuracy. This advanced procedure is performed without the need for the stereotactic head frame that is used in other radiosurgical treatments. Thereby reducing the overall treatment time, and anesthesia is unnecessary and the process is painless and comfortable. Also, because the CyberKnife does not require a stereotactic head frame, a CyberKnife treatment can be delivered in several fractions (up to five sessions), if necessary, to spare surrounding healthy tissue.

Yet, CyberKnife goes beyond intracranial lesions. Because highly-accurate, stereotactic Radiosurgery is achieved without a head frame, the ability to treat Radiosurgically now includes tumors and lesions of the spine. At the CyberKnife Institute at Mercy Hospital, we use the very latest CyberKnife hardware and software, including the world’s first next-generation linear accelerator. In other words, we have the power to treat more patients with improved accuracy, in less time, and with less patient risk and discomfort than is possible with other forms of radiosurgery.

http://www.cyberknifemercy.org/cyberknife-brain-tumor-treatment.asp

The CyberKnife is a frameless robotic radiosurgery system used for treating benign tumors, malignant tumors and other medical conditions. The system was invented by John R. Adler, a Stanford University Professor of Neurosurgery and Radiation Oncology, and Peter and Russell Schonberg of Schonberg Research Corporation. The two main elements of the CyberKnife are the radiation produced from a small linear particle accelerator and a robotic arm which allows the energy to be directed at any part of the body from any direction.

The CyberKnife system is a method of delivering radiotherapy, with the intention of targeting treatment more accurately than standard radiotherapy.

 

Log in or Sign up to hide all adverts.

Here is a great new paper on the topic on PLOS [full text free]:


Cancer Screening by Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression

And an article on the same at Scientific American

Basically it involves using an altered virus (herpes) to seek out and induce cancer cells to secrete a blood biomarker for cancer which can be easily detected by simple tests on blood and urine. The biomarker is Gaussia luciferase.

The method:

Please Register or Log in to view the hidden image!

 

Log in or Sign up to hide all adverts.

"A large-scale, retrospective study published in the JNCI has now shown that men who take statins had lower incidence of total and high-grade prostate cancer compared with men who took antihypertensive medications. ...
The statin cohort was 60% less likely to develop high-grade prostate cancer and 14% less likely to develop low-grade prostate cancer. Additionally, high levels of serum cholesterol were associated with higher risk for both high-grade and overall prostate cancer. ..."

From: http://www.cancernetwork.com/prosta...A4-B792-533D454302E8&rememberme=1&ts=13052011

BT comment Men taking satins tend to be men with high cholesterol. Perhaps the reduced risk of PCa, in part or total, is due to the reduction in cholesterol the Satins achieved?

 

Advanced Drug-Delivery Systems of Curcumin for Cancer Chemoprevention
...Abstract

From ancient times, chemopreventive agents have been used to treat/prevent several diseases, including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, anti-oxidant, anti-proliferative, anti-carcinogenic, and anti-angiogenic activity in various cell culture and some animal studies. Research over the past four decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell-culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been demonstrated to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician's armamentarium.

From: http://cancerpreventionresearch.aac...ly/2011/04/26/1940-6207.CAPR-10-0006.abstract

 

Coffee has been linked to a reduced risk of dying from prostate cancer in a study of nearly 50,000 US men. Those who drank six or more cups a day were found to be 20% less likely to develop any form of the disease - which is the most common cancer in men. They were also 60% less likely to develop an aggressive form which can spread to other parts of the body. But even relatively small amounts of coffee - one to three cups per day - were found to lower the risk of lethal prostate cancer by 30%. No difference was seen between caffeinated and decaffeinated coffee, suggesting caffeine itself was not the cause.

But charities say the evidence, reported in the Journal of the National Cancer Institute, is still unclear. They do not recommend that men take up coffee drinking in the hope of preventing prostate cancer.

The study looked at about 48,000 men in the US who work as health professionals. Every four years between 1986 and 2006, they were asked to report their average daily intake of coffee. During this 20-year period, 5,035 of the men were diagnosed with prostate cancer, including 642 fatal cases. Each year about 37,000 men are diagnosed with prostate cancer in the UK Some 10,000 die from the disease
...
The researchers think there may be unknown compounds in coffee that protect against the disease. Lead researcher Dr Kathryn Wilson, from the Harvard School of Public Health in Boston, said: "At present we lack an understanding of risk factors that can be changed or controlled to lower the risk of lethal prostate cancer.

from: http://www.bbc.co.uk/news/health-13430219

 

May 18 (Reuters) - Exelixis Inc's experimental cancer drug cabozantinib was shown in a mid-stage trial to help control advanced prostate, ovarian and liver cancers, according to research presented on Wednesday. The drug was also found to fully or partly eliminate cancer that had spread to the bone in patients with breast cancer, prostate cancer and melanoma, according to the American Society of Clinical Oncology, which featured the data ahead of its annual meeting in June.

"We saw unprecedented bone scan improvement," said the study's lead author Dr. Michael Gordon, a medical oncologist at Pinnacle Oncology Hematology in Scottsdale, Arizona. Cabozantinib, also known as XL184, is the lead product for Exelixis, which has seen its shares nearly double since announcing in November positive trial results in prostate and ovarian cancers. It is an oral drug designed to block the pathway that tumors need to form new blood vessels ..."

I have long owned shares in EXEL. BMS made big mistake on 21June10: Exelixis and BMS not able to agree on development of XL184. BMS will return of XL184 and pay Exelixis of $17E6. In 2008, BMS announced it would pay Exelixis $195E6 and another $45 million in 2009 to co-develop XL184 and XL281.

Here (a tiny part of my notes) is status of other drugs in their pipline as of Oct2010 (each line after the first tells the clinical trials):
XL1472 target = PI3K Sanofi-Aventis
Endometrial Cancer Phase 2
Breast Cancer + trastuzumab +/- paclitaxel Phase 1b/2
NSCLC + erlotinib Phase 1b/2
Solid Tumors + paclitaxel/carboplatin Phase 1b/2
Solid Tumors Phase 1

XL7652 target = PI3K & mTOR Sanofi-Aventis
GBM + temozolomide Phase 1b/2
NSCLC + erlotinib Phase 1b/2
Soid Tumors Phase 1

XL1391 target = Hedgehog BMS only as EXEL opted out of co-development but get miles stones (for quiting?)
Gastric Cancer + cisplatin + capecitabine Phase 1b
SCLC + carboplatin + cisplatin Phase 1b
Multiple Myeloma + lenalidomide or bortezomib Phase 1b
Solid Tumors Phase 1

XL4131 target = Cdc7 Bristol-Myers Squibb
Solid Tumors Phase 1
Hematologic Malignancies Phase 1

XL888 target = HSP90 Unpartnered
Cancer Phase 1

XL499 target = PI3Kδ Unpartnered
Cancer and Inflammation Preclinical

1. In co-development agreement with BMS, Exelixis funds 35% of development costs (except for Japan) and will share 50% of any future profits from future Unites States sales and will be eligible for milestones and royalties from future ex-Unites States sales.
2. Out-licensed to sanofi-aventis. Exelixis currently conducts the majority of clinical development but is reimbursed for 100% of its costs and is eligible to receive milestones and royalties on future product sales.

30May09 Exelixis Inc. said Thursday it will collaborate with French drugmaker Sanofi-Aventis to develop cancer treatments in a deal that could be worth more than $1 billion.

 

" Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), {is} developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today announced interim median overall survival of 8.8 months (38 weeks, 40 patients at first relapse) from a Phase II trial for Cotara® in recurrent glioblastoma multiforme (GBM). " {BT notes: GMB is the most common and serious brain tumor.}

 

"... FDA today approved {Vertex's} Incivek (telaprevir) to treat certain adults with chronic hepatitis C infection. Incivek is used for patients who have either not received interferon-based drug therapy for their infection or who have not responded adequately to prior therapies. Incivek is approved for use with interferon therapy made up of peginterferon alfa and ribavirin. ..."

Merck had its new Hep C drug FDA approved about two weeks ago. Both are "near miracles" as have high cure rates in about two weeks instead of low cure rates with months or even years of treatments.

Unfortunately they are expensive - near $50,000 for your cure, but as I am a long time holder of stock in Vertex (from years ago when their drug was called VX-950, three names back) I know they spent approximately 4 BILLION DOLLARS developing it. Global sales are expected to soon reach ~3 billion per year so it all turned out well, for all. IMHO, it is a little better, more effective than Merck's new drug, but also priced slightly higher.

 

"... Cancer is worsening in China, where it causes an annual 2.1 million deaths. That’s luring overseas researchers intent on meeting surging demand for treatments. BeiGene Ltd. hired 20 U.S.-educated scientists from companies including Johnson & Johnson and Merck & Co. to help find new cancer medicines since it formed last July. ..." From: http://noir.bloomberg.com/apps/news?pid=20601087&sid=aMmzcP5xv1PY&pos=7

As I have noted in other threads, China has funds, and is using them to buy the best western brains to lead their research and staff their new universities - quicker than educating them but doing that on an enormous scale too, however it takes too long to locally produce the top of the field level people so China just buys them or even the companies they work for.

In its early years GE, wanted to hire the genius Steinmetz who worked for a German friend in his small company. That friend had payed for him to come to the USA. GE offered many times his salary, but he was loyal to his friend, so GE bought the whole company to get Steinmetz! - China is doing the same especially to learn the technology of horizontal drilling and "fractoring" for natural gas in shale deposits.

 

More, much more, related to post 29"s PS-targeting antibody technology:

"Our research shows that exposed PS in the tumor environment plays a fundamental immunosuppressive role that prevents the immune system from recognizing cancer cells as 'foreign,' resulting in cancer patients not being able to reject their tumors," said Philip E. Thorpe , Ph.D., professor of pharmacology in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center , scientific adviser to Peregrine and inventor of the company's PS-targeting antibody technology. "We show that highly immunosuppressive cells called myeloid-derived suppressor cells, or MDSCs, accumulate in tumors and fail to mature into functional immune cells. What is especially exciting is that administration of PS-targeting antibodies like bavituximab breaks the grip of the tumor on the immune system. In treated animals, we see the disappearance of MDSCs and the appearance of functional immune cells, especially macrophages. The entire tumor environment shifts from being immunosuppressive to being immune responsive. These results have important implications for cancer therapy."

Peregrine has been asked to give the keynote address to the 10th Annual Informa Life Sciences Recombinant Antibodies Conference in Barcelona, Spain.

The abstract can be accessed through the conference website http://www.informaglobalevents.com/event/antibodies1 and slides from this keynote address can be found on Peregrine's website at www.peregrineinc.com under "Features." About Bavituximab

 

"... we describe the development of prostate-targeted RNAi agents that selectively sensitized prostate-specific membrane antigen–positive (PSMA-positive) cells to IR. siRNA library screens identified DNA-activated protein kinase, catalytic polypeptide (DNAPK) as an ideal radiosensitization target. DNAPK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNAPK in PCa cells, xenografts, and human prostate tissues. Aptamer-targeted DNAPK shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. These findings support aptamer-shRNA chimeras as selective sensitizing agents for the improved treatment of high-risk localized PCa. ..." form: http://www.jci.org/articles/view/45109

Here is BT's translation aid:

RNA is sort of half of DNA, the i after (or before) indicates that something is interfering with the normal function of that RNA. They have joined some RNAi agent to a molecule that selectively attaches to parts of prostate cancer cells. Also adjoined to this targeting molecular complex is a sh = short hair pin molecule which I think acts like an recieving anntena or high cross section target for the IR = ionizing radiation, that locally makes reactive ions that help kill the cell.

They have demonstrated their complex agent aids to selective kill cancer cell (presumably at lower IR doses so less damage is done to nearby normal cells) both in vitro and in mice with human prostate cancer cells.

 

"...abiraterone acetate plus prednisone/prednisolone showed a significant improvement in overall survival compared to patients treated with prednisone/prednisolone plus placebo. ..." from: http://www.therapeuticsdaily.com/ne...e=784385&contentType=newsarchive&channelID=26

 

Scientists cure cancer, but no one takes notice

Until recently, researchers believed that cancer-affected mitochondria are permanently damaged and that this damage is the result, not the cause, of the cancer. But Michelakis, a cardiologist, questioned this belief and began testing DCA, which activates a critical mitochondrial enzyme, as a way to "revive" cancer-affected mitochondria.

The results astounded him.

Michelakis and his colleagues found that DCA normalized the mitochondrial function in many cancers, showing that their function was actively suppressed by the cancer but was not permanently damaged by it.

More importantly, they found that the normalization of mitochondrial function resulted in a significant decrease in tumor growth both in test tubes and in animal models. Also, they noted that DCA, unlike most currently used chemotherapies, did not have any effects on normal, non-cancerous tissues.

http://www.dca.med.ualberta.ca/Home/Updates/2007-03-15_Update.cfm

 

"... The University of Alberta's DCA Research Team is set to launch clinical trials on humans in the spring of 2007 pending government approval. Knowing that thousands of cancer patients die weekly while waiting for a cure, Dr. Michelakis and his team are working at accelerated speed, condensing research that usually takes years into months. Fundraisers at the University of Alberta are determined to raise the money to allow this next phase of research to begin. Once Health Canada grants formal approval, the University of Alberta's Research Team will begin testing DCA on patients living with cancer. Results with regards to the safety and efficacy of treatment should be known late this year. ..." From: http://www.dca.med.ualberta.ca/Home/Updates/2007-03-15_Update.cfm (Spidergoat’s last ref.)

Note following text is from Nov 2010 Ref. And still no important proof of effectiveness against cancers – only a hint in five patient with no controls – or possibility to tell from chance results:

“…DCA inhibits an enzyme called pyruvate dehydrogenase kinase. The effect of that inhibition is to move metabolism away from lactic acid-producing glycolysis and toward more normal oxidation of glucose in the mitochondria, the energy factories of the cell.
In 2007, Dr. Michelakis and colleagues published a paper showing that DCA, when put in drinking water, could slow the growth of human lung tumors implanted into rats. It seemed the DCA did not affect normal cells. {Billy T notes “tumors" need not be cancers}
… Some clinics {and chemists} still offer it. Dr. Michelakis cautioned that in high doses DCA can cause nerve damage and that it takes months for enough to build up in the body to have any effect.

This spring, {2010} in the journal Science Translational Medicine, Dr. Michelakis reported results of the first human testing of DCA, in five patients with glioblastoma multiforme, a deadly brain cancer. There was no control group, making it hard to judge the drug’s effectiveness, though some patients lived longer than might have been expected. … {and BT suspects: some of the five lived less than average?}

Since DCA is not a novel compound, it cannot be patented, making it unlikely a pharmaceutical company would pay for clinical trials. So Dr. Michelakis has been raising money from foundations and governments to conduct larger clinical trials. “We have only assumptions and theoretical excitement,” Dr. Michelakis said. Still, he added, “there’s no question that this is a new direction that is logical and very appealing.” ..."

From: http://www.nytimes.com/2010/11/30/health/30cancer.html?_r=1&hp=&pagewanted=all {article was on page D-1}

Spider’s first link is a very optimistic for DCA. It contains this drawing of how it works, in theory (but there is as of yet no real proof that it does).

Please Register or Log in to view the hidden image!

While drug companies will not spend money properly testing public domain chemicals, the heath insurance companies would be ramming the cheap to make DCA down cancer patient's throats if they had reason to think it cured cancer.

BTW, it is not just the metabolic processes of sugars that differ in fast dividing cancer cells (or as SAM noted in the same way in normal cells when stressed by say prolonged exercise that make the normal utilization of sugars too slow) but I think the fact that their telemers don't shorten with each cell division is very different an important and what gives them immortality.

 

"... Bayer's investigational compound, radium-223 chloride, ... in patients with castration-resistant prostate cancer (CRPC) and bone metastases met its primary endpoint by significantly improving overall survival. Based on a recommendation from the Independent Data Monitoring Committee (IDMC), following a pre-planned interim analysis, the study will be stopped and patients on the placebo arm will be offered treatment with radium-223 chloride.

The overall survival result was statistically significant (two-sided p-value = 0.0022, HR = 0.699, the median overall survival was 14.0 months for radium-223 chloride and 11.2 months for placebo). ... "

From: http://pharmalive.com/news/index.cfm?articleID=785916&categoryid=9&newsletter=1

BT comment: Assuming radium-223 emits ionizing radiation, how does it compare in cost, safety and effectiveness to same externally applied radiation?

 

FDA warns that drugs commonly used to treat benign prostatic hyperplasia (BPH) often lead to more serious prostate cancers.
See: http://pharmalive.com/news/index.cfm?articleID=787168&categoryid=9&newsletter=1

 

“…Peregrine Pharmaceuticals has reported promising median overall survival (MOS) of 12.4 months from a Phase II clinical trial evaluating bavituximab plus carboplatin and paclitaxel in patients with previously untreated, locally-advanced or metastatic non-small cell lung cancer. This survival is 20% longer than the 10.3 month MOS from a separate historic control trial using carboplatin and paclitaxel alone in a similar patient population. ... "
Read more at: http://www.therapeuticsdaily.com/ne...992668&contentType=sentryarticle&channelID=26

Billy T comment: Good work, shows progress, better understanding, etc. but treatment gaining 2.1 months more life on average at what dollar price?

 

"... The development of prostate cancer (PCa) and its progression to castrate-resistant prostate cancer (CRPC) after anti-androgen ablation therapy are driven by persistent biological activity of androgen receptor (AR) signaling. Moreover, studies have shown that more than 50% of human PCa over-express ERG due to AR-regulated TMPRSS2-ERG fusion gene. ... We found that activation of AR resulted in the induction of ERG expression through TMPRSS2-ERG fusion.

Moreover, we found that ERG over-expression and nuclear translocation activated the activity of Wnt signaling. Furthermore, forced over-expression of ERG promoted invasive capacity of PCa cells. ... Based on our findings, we conclude that because BR-DIM and CDF down-regulate multiple signaling pathways including AR/TMPRSS2-ERG/Wnt signaling, these agents could be useful for designing novel strategies for the prevention and/or treatment of PCa.
From: http://cancerpreventionresearch.aac...ly/2011/06/15/1940-6207.CAPR-11-0077.abstract {only the full abstract is free}

 

"... “Stupid cancers,” which have been a large focus of research in the era of targeted therapy, are those with a low mutational load and a single “driver” mutation. The discovery of a drug that targets that driver mutation is a reliable formula for success in stupid cancers, ...

“Smart cancers,” on the other hand, have a high mutational load (from 10 to as many as 100 mutations per megabase) and multiple drivers. Unfortunately, many common cancers are smart cancers. Among the best known examples are non–small-cell lung cancer (NSCLC) and melanoma. ... Another “smart” feature of cancers that is being revealed by genomic studies is the ability to evolve: primary tumors can give rise to metastases and secondary metastases that are genetically different from the tumor from which they derive. ..."

From outgoing president of ASCO, Dr. George Sledge: http://www.cancernetwork.com/confer...A4-B792-533D454302E8&rememberme=1&ts=17062011

ASCO = American Society for Clinical Oncology had Annual Meeting, Saturday June 4, 2011 where Dr. Sledge gave keynote address. His main point being that treatment of cancer was now entering a new era, with complete genome measurement (of cancer cell too) cost approaching $1000.