Taxol reduces cell regeneration obstacles after spinal cord injury...

Scientists of the Max Planck Institute of Neurobiology in Martinsried and their colleagues from the Kennedy Krieger Institute and University of Miami in the United States, and the University of Utrecht in the Netherlands, have now shown that the cancer drug Taxol (see structure)  reduces both regeneration obstacles. Frank Bradke and his team at the Max Planck Institute of Neurobiology in Martinsried study the mechanisms inside CNS nerve cells responsible for stopping their growth. As per the claim by the researchers,  protein tubes (micro tubules) have a parallel arrangement in the tip of growing nerve cells, stabilizing cells and actively pushing the cell end forward. This arrangement is lost in injured CNS cells. So how can the order of the microtubule be kept or regained in these cells? And once the cells start growing, how can they overcome the barrier of the scar tissue? Together with their colleagues from the United States and the Netherlands, the Max Planck scientists have now found a common solution for both problems. Taxol, the trade name of a drug currently used for cancer treatment, has now been shown to promote regeneration of injured CNS-nerve cells.

Researchers claim that,  Taxol promotes regeneration of injured CNS-nerve cells in two ways: Taxol stabilizes the microtubules so that their order is maintained and the injured nerve cells regain their ability to grow. In addition, Taxol prevents the production of an inhibitory substance in the scar tissue. The scar tissue, though reduced by Taxol, will still develop at the site of injury and can thus carry out its protective function. Yet growing nerve cells are now better able to cross this barrier. 

"This is literally a small breakthrough", says Bradke.

Experiments in rats performed by this group verified the effects of Taxol. These researchers supplied the injury site after a partial spinal cord lesion with Taxol via a miniature pump. After just a few weeks, animals showed a significant improvement in their movements. So far researchers  tested the effects of Taxol immediately after a lesion.  Researchers next plan  is to investigate whether Taxol is as effective when applied onto an existing scar several months after the injury.  As the research is still in the state of basic research and a variety of obstacles remain  and eventually, pre-clinical trials will need to be done,  "however,  researchers believe that this is a very promising path........

Ref: Farida Hellal et. al., 

New efficient synthesis for Taxol ?

In continuation of my update on taxol....

Baran's group reports erecting that Rockefeller tree and adding the first few ornaments -- a molecule called taxadiene. A conventional taxadiene synthesis is inefficient and involves 26 steps to produce. The Baran group's method involves just 10 steps to produce many times what has been previously synthesized -- more than sufficient for planned research to find a way to efficiently produce Taxol®.

Innovation Leads to Access.....

The taxadiene synthesis is more than just a midway stop on the way to Taxol®. The current commercial Taxol® production method, which involves culturing cells from the yew tree, is more economical than any new synthesis is likely to be. Instead, Baran and his team are aiming to understand the processes used in nature to produce the compound, which are many times more efficient than those used by scientists to date. "It's my opinion that when there's a huge discrepancy between the efficiency of nature and humans, in the space between, there's innovation.

More specifically, lead researcher Phil Baran believes that, while developing an efficient synthesis for Taxol®, they will gain a fundamentally improved understanding of the chemistry involved and develop more widely applicable techniques. Such innovation could allow production of a whole range of taxanes currently inaccessible for drug discovery research either because the quantities researchers can produce are vanishingly small, or because they can't produce them at all. Control of the taxane oxidation process therefore offers the potential for discovering new and important drugs, perhaps even one or more that is better at fighting specific cancers than Taxol®.

Establishing the remaining steps between taxadiene and Taxol® or other more complex taxanes remains a challenging task that Baran estimates will take years.

"Nature has a choreography in the way she decorates the tree," he said. "It's a precise dance she has worked out over millennia. We have to figure out a way to bring that efficiency to the laboratory setting."

More... : http://www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.1196.html

New details on microtubules and how the anti-cancer drug Taxol works

A pathway to the design of even more effective versions of the powerful anti-cancer drug Taxol has been opened with the most detailed look ever at the assembly and disassembly of microtubules, tiny fibers of tubulin protein that form the cytoskeletons of living cells and play a crucial role in mitosis. Through a combination of high-resolution cryo-electron microscopy (cryo-EM) and new methodology for image analysis and structure interpretation, researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley have produced images of microtubule assembly and disassembly at the unprecedented resolution of 5 angstroms (Å). Among other insights, these observations provide the first explanation of Taxol's success as a cancer chemotherapy agent.

New details on microtubules and how the anti-cancer drug Taxol works  

Preclinical studies shows EmPAC more effective than Taxol

Cornerstone Pharmaceuticals, Inc. has announced the publication of data from preclinical studies on EmPAC™ (nanoparticle reformulation of paclitaxel). Company claims the data demonstrating improved safety and efficacy of EmPAC™ versus Taxol®, the generic formulation of paclitaxel and one of the most widely prescribed chemotherapies. EmPAC™ is a nanoemulsion formulation of Paclitaxel and is the lead product candidate of Cornerstone’s proprietary Emulsiphan™ cancer selective delivery nanotechnology platform. Taxol®, an injectable formulation of Paclitaxel, is currently used to treat a variety of cancers, including ovarian carcinomas, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi’s sarcoma....

More : http://www.cornerstonepharma.com/wp-content/uploads/Empac-JNN-Release-FINAL-Sept_15_2011.pdf

Antisense drug in combination with paclitaxel for prostate cancer..

I think when I was doing some reference work for my research in 1996, I read about this drug (taxol) [In 1994 the total synthesis has been achieved by Robert Holton of Florida University. He did spend 12 years to achieve the total synthesis because of the assymmtery involved in it [It was after 40 years' after the first exctract from the tree Pacific yew (Taxus brevifolia) has shown anticancer activity and the key ingrediant identified was taxiol]. A diterpenoid, with androgen (a male hormone) blockade chemotherapy has played important role in the treatment of cancer.

Prostate cancer is the second most frequently diagnosed cancer in men after skin cancer. It is estimated there will be 218,890 new cases diagnosed in the U.S. this year(2009). Around 1 in 6 men will develop prostate cancer, a third to a half of whom will recur after local treatment and risk progression to metastatic prostate cancer. Metastatic disease invariably progresses to hormone refractory or castrate resistantprostate cancer (CRPC) if given enough time.

Prostate tumours are initially androgen (male sex hormone) dependent, and can be treated with androgen ablation therapy, however once the disease progresses to its most dangerous and aggressive form, CRPC, treatment options are limited and prognosis is poor. Treatment options depend on disease severity and include radiation and chemotherapy, which are designed to induce programmed cell death (apoptosis) of tumour cells. There is a pressing need for the development of new treatment options.

More interesting and significant results have been achieved by an Australian company (Antisense Therapeutics). i.e., in combination with taxol, antisense drug ATL1101 has yielded good results. ATL1101 is a second generation antisense inhibitor of the insulin-like growth factor-I receptor (IGF-IR) which as reported previously suppressed the growth of human prostate tumors in an animal model of prostate cancer, and slowed down transition to CRPC when used as a single agent.

The research is of great importance because of the fact that in cell culture experiments, the amount of Paclitaxel required to induce tumor cell apoptosis (cell death) was significantly reduced when used in combination with ATL1101. This ability to 'sensitize' tumor cells to the cytotoxic effects of Paclitaxel affirms ATL1101's potential as a chemo-sensitizing agent to be used in combination with existing prostate treatments to improve the outcomes for patients.

I did work for some of the intermediates (ologonucleotides) for ISIS (contract research) and am excited to see that this company has tie up with ISIS. In my opinion as ISIS , is an established company in this field of research, hope soon there will be relief for those patients for whom CRPC, treatment options are limited and prognosis is poor....

Ref: http://www.antisense.com.au/!upload_files%5Cattachment%5Casx%2009%2018%20June%202009_ATL1101.pdf

2 Pre-Surgery Drug Treatments Show Promise Against Aggressive Breast Cancer - Drugs.com MedNews

This pre-surgical drug therapy boosts the likelihood that no cancer cells will be found in breast tissue removed during either mastectomy or lumpectomy, according to two new studies.

The approach, called "neoadjuvant" chemotherapy, is being given to an increasing number of women with what's known as triple-negative breast cancer. Currently, the approach results in no identifiable cancer cells at mastectomy or lumpectomy in about-one third of patients, experts estimate. In such cases, the risk of a tumor recurrence becomes lower.

"Chemotherapy [before surgery] does work in triple-negative breast cancer. What we want to do is make it work better," said study researcher Dr. Hope Rugo.

Rugo is director of breast oncology and clinical trials education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

Triple-negative cancers have cells that lack receptors for the hormones estrogen and progesterone. In addition, they don't have an excess of the protein known as HER2 on the cell surfaces. So, treatments that work on the receptors and drugs that target HER2 don't work in these cancers.

In two new studies, researchers got better results by adding drugs to the standard chemo regimen prior to surgery. However, both studies are phase 2 trials, so more research is needed.

Both studies are due to be presented Friday at the annual San Antonio Breast Cancer Symposium.

Rugo compared standard neoadjuvant therapy -- paclitaxel (Taxol, others), doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan, others) -- to standard therapy plus the drugs veliparib (investigational) and carboplatin (Paraplatin)....

2 Pre-Surgery Drug Treatments Show Promise Against Aggressive Breast Cancer - Drugs.com MedNews

Paclitaxel drug may promote cancer spread at low doses

In continuation of my update on paclitaxel

New research indicates that paclitaxel, which is the most commonly used chemotherapy for breast cancer, suppresses tumors when given at a certain dosage, but at low doses, it actually promotes cancer spread to the liver.

The findings suggest that lowering the dose of paclitaxel to reduce toxic side-effects is not a safe strategy.

"Paclitaxel and its analogous compounds are the first line agents widely used in clinical cancer chemotherapy. However, potential risks and reasonable treatment strategies of paclitaxel continue to be widely investigated," wrote the authors of The FEBS Journalstudy.

http://onlinelibrary.wiley.com/doi/10.1111/febs.13767/full

Palbociclib and paclitaxel combination shrinks tumors in patient with ER positive breast cancer

Combining the new breast cancer drug palbociclib with paclitaxel (Taxol) shrank tumors in nearly half of patient with estrogen-receptor (ER) positive breast cancer, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The results will be presented Saturday at the 2015 San Antonio Breast Cancer Symposium (Abstract P6-13-08). A second study (Abstract P4-13-04), to be presented Friday provides new clues to how breast cancer develops resistance to the palbociclib, a common occurrence among many patients who take the drug.

"Results of the first study found that palbociclib and paclitaxel can be safely combined on an alternating dosing schedule," said Angela DeMichele, MD, MSCE, the Alan and Jill Miller Associate Professor in Breast Cancer Excellence in Penn's Abramson Cancer Center, and senior author on the study. "The high response rate we saw suggests this combination may hold benefits for patients over paclitaxel alone. Based on these results, a larger clinical trial to determine the benefits is warranted."

A Complementary Therapy

Palbociclib targets the rapid division of tumor cells by inhibiting the activity of the enzymes CDK4 and CDK6, which help drive cell division and are upregulated in most cancers. The researchers suspected that palbociclib's unique mechanism of action may make it a good partner for other breast cancer drugs such as paclitaxel, which kills dividing cells at a certain point in the cell division process (also known as the "cell cycle"). Palbociclib effectively halts the cell cycle before that point, and thus in principle can synchronize cancer cells in a way that makes them more vulnerable to a closely following dose of paclitaxel.

Palbociclib and paclitaxel combination shrinks tumors in patient with ER positive breast cancer

Combination therapy provides promising results in patients with advanced non-small cell lung cancer

An early phase study testing an anti-PDL1 agent in combination with standard chemotherapy in the treatment of advanced non-small cell lung cancer has provided promising early results, prompting multiple phase III studies in lung cancer. The findings are being presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

In this phase 1b study, patients with untreated non-small cell lung cancer received one of three standard platinum-based chemotherapy regimens (paclitaxel/carboplatin, pemetrexed/carboplatin or nab-paclitaxel/carboplatin) with MPDL3280A, an antibody targeting PD-L1. Early results from the 

Paclitaxel Carboplatin Pemetrexed

first 37 patients showed impressive response rates between 60-75 percent, comparing favorably to historical outcomes with chemotherapy alone, where historical response rates from randomized trials are around 30 - 35 percent. In addition, two complete responses already have been documented, with no evidence of lung cancer on CT scans.

"A complete response is not typically seen in patients with stage IV lung cancer," says the abstract's lead author, Stephen V. Liu, MD, assistant professor of medicine at Georgetown Lombardi Comprehensive Cancer Center. "And the response rates seen with MPDL3280A and chemotherapy were higher than one would expect with chemotherapy alone."

Combination therapy provides promising results in patients with advanced non-small cell lung cancer

New drug combination before surgery may improve outcomes in breast cancer patients

 

In continuation of my update on Paclitaxel 

Results from the I-SPY 2 trial show that giving patients with HER2-positive invasive breast cancer a combination of the drugs trastuzumab emtansine (T-DM1) and pertuzumab before surgery was more beneficial than the combination of paclitaxel plus trastuzumab. Previous studies have shown that a combination of T-DM1 and pertuzumab is safe and effective against advanced, metastatic HER2-positive breast cancer, but in the new results, investigators tested whether the combination would also be effective if given earlier in the course of treatment. Results of the study are presented by trial investigators from the Abramson Cancer Center at the University of Pennsylvania at the AACR Annual Meeting 2016, April 16-20.

In this latest phase of the I-SPY2 trial, investigators worked to determine whether T-DM1 plus pertuzumab could eradicate residual disease (known as pathological complete response, or pCR) for more patients if delivered before surgery to shrink cancer tumors compared with paclitaxel plus trastuzumab. They also examined whether this combination could meet that goal without the need for patients to receive paclitaxel.

"The combination of T-DM1 and pertuzumab substantially reduced the amount of residual disease in the breast tissue and lymph nodes for all subgroups of HER2-positive breast cancers compared with those in the control group," said lead author, Angela DeMichele, MD, MSCE, a professor of Medicine and Epidemiology at the Perelman School of Medicine at the University of Pennsylvania, who will present the findings. "Our results suggest a possible new treatment option for patients that can not only effectively shrink tumors in the breast, but potentially reduce the chance of the cancer coming back later. The results also show that by replacing older, non-targeted therapies with more effective and less-toxic new therapies, we have the potential to both improve outcomes and decrease side effects."

For the study, patients whose tumors were 2.5 cm or bigger were randomly assigned to 12 weekly cycles of paclitaxel plus trastuzumab (control) or T-DM1 plus pertuzumab (test). Following the initial test period, all patients received four cycles of the chemotherapies doxorubicin and cyclophosphamide, and surgery. Patients' tumors were then tested for one of three biomarker signatures: HER2-positive, HER2-positive and hormone receptor (HR)-positive, and HER2-positive and HR-negative.

New drug combination before surgery may improve outcomes in breast cancer patients: Results from the I-SPY 2 trial show that giving patients with HER2-positive invasive breast cancer a combination of the drugs trastuzumab emtansine (T-DM1) and pertuzumab before surgery was more beneficial than the combination of paclitaxel plus trastuzumab.