Researchers able to predict and reverse resistance to Sunitinib treatment....

Van Andel Research Institute (VARI) researchers have found a way to  reverse resistance to Sunitinib (see structure), a treatment that is currently the first line of defense against clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Most patients who show a positive response to Sunitinib develop a resistance to the drug after one year of treatment.

Researchers lead by Dr. Teh, Bin Tean found that ccRCC tumor cells that had developed a resistance to Sunitinib had increased secretion of the protein interleukin-8 (IL-8). Administering Sunitinib and IL-8 neutralizing antibodies re-sensitized tumors to sunitinib treatment. Researchers also found that IL-8 may serve as a useful biomarker to predict patients' response to sunitinib treatment.

Interestingly,  another  study from same  group  of  Teh’s laboratory, looked into exactly how sunitinib works.  The study found that the treatment does not target tumor cells, but rather the tumor’s blood supply.

Researchers conclude that “it is now of critical importance to validate these findings in the clinical setting" and they hope that these insights will help to build upon recent advances to extend clinical benefits to more patients with metastatic kidney cancer....

Ref : 1.  Cancer Research 70, 1053, February 1, 2010. 

        2.  Cancer Research 70, 1063, February 1, 2010

New strategy to overcome drug resistance (tamoxifen) in breast cancer ?

A solution to tamoxifen resistance is sorely needed, and if a strategy like this can work, it would make a difference in our clinical care of breast cancer,” says the study’s lead investigator. Yes, the researchers lead by Dr. Robert Clarke of Georgetown Lombardi Comprehensive Cancer Center have come with an interesting finding i.e., combining tamoxifen, the world’s most prescribed breast cancer agent  with a compound (Parthenolide,  see left structure source : ChemSpider) found in the flowering plant feverfew (right picture) may prevent initial or future resistance to the drug. 

 

As per the claim by the researchers tamoxifen resistance is regulated by the protein complex NF- κB (nuclear factor kappa B), which is often found to be over-expressed in ER+ breast cancer. NF- κB is known to help cells survive when damaged. Earlier the same researchers have also found that, the resistance to another tamoxifen-like drug, fulvestrant, was controlled by a protein (Bcl2) which is also regulated by NF- κB. These findings  encouraged  them to think that,  blocking NF- κB might affect tamoxifen resistance. 

Researchers conducted a variety of tests using parthenolide, which has been shown to act on NF- κB. They found that in resistant breast cancer cells, the chemical blocked the activity of NF- κB, making the cells sensitive once again to tamoxifen. Researchers then silenced NF- κB in tamoxifen resistant cells, and found that this had the same effect as using parthenolide. 

They further found that increased activation of NF- κB can alter sensitivity of tamoxifen by modulating the protein CASP8 (which is involved in programmed cell death), which affects Bcl2  and there by  helping  to  push a damaged cell to die.  
 

About Feverfew : 

Feverfew (Tanacetum parthenium) is edible and medicinal plant and   has a good reputation as alternative medicine and extensive research has proved it to be of special benefit in the treatment of certain types of migraine headaches and rheumatism or arthritis. The plant is rich in sesquiterpene lactones, the principal one being parthenolide. Parthenolide helps prevent excessive clumping of platelets and inhibits the release of certain chemicals, including serotonin and some inflammatory mediators. (other constituents are: pinene, pinene derivatives, bornylacetate, angelate, b-farnesine, spiroketalenol ethers, flavonoid glycosides and costic acid) .

Though the leaves and flowering heads are reported to possess antiinflammatory, antispasmodic, aperient,  sedative, stimulant, stomachic, vasodilator and vermifuge. activities, this type of activity has been reported  for the first time. 

 

Researchers conclude that the chemical, clearly has the potential to be able to figure out fairly  and it can help solve tamoxifen’s resistance problem with a caution that the science is much too early to make any recommendations. Let us wait for some more time.......

Ref :  Robert Clarke et. al., Feb. 12 in FASEB

Positive phase II clinical results of abiraterone (for advanced prostate cancer)....

We know that,  Abiraterone (discovered and developed at the Institute of Cancer Research in London, see structure) is a drug under investigation for use in hormone-refractory prostate cancer (prostate cancer not responding to treatment with antiandrogens). Abiraterone acts  by blocking the formation of testosterone by inhibiting CYP17A1 (CYP450c17), an enzyme also known as 17α-hydroxylase/17,20 lyase.  This enzyme is involved in the formation of DHEA and androstenedione, which may ultimately be metabolized into testosterone.

 

The latest trial, which was led by the ICR and the Royal Marsden  NHS Foundation Trust, is the first to investigate the drug in men with such advanced prostate cancer.

A total of 47 men were recruited for the trial, all of whom had late-stage castration-resistant prostate cancer, which means that their disease was advanced and their tumors were no longer responsive to androgen deprivation therapy. In almost all cases, the men's cancer had spread to their bones. All of the participants had already received hormone therapy and the chemotherapy drug docetaxel, but were no longer responding to those treatments. By the end of the study period, researchers found that around three-quarters of men had experienced a drop in levels of prostate specific antigen (PSA), which is often raised in men with prostate cancer and can be used to measure disease activity.

 In around half of the men,  PSA levels fell by at least 50 per cent, while three-quarters of participants also had a drop in the number of tumor cells circulating in their blood. Three years after the start of the trial, five of the patients were still taking abiraterone and benefitting from the treatment. Lead researcher Dr Alison Reid, also from the ICR and the Royal Marsden, noted that "abiraterone shrank or stabilised men's cancers for an average of almost six months, which is a very impressive result with only mild side-effects". 

Though the initial results are exciting, the researchers conclude that there's a lot more work needed to establish what abiraterone's place will be in treating men with prostate cancer....

Ref :http://info.cancerresearchuk.org/news/archive/cancernews/2010-02-16-New-drug-shows-promise-for-advanced-prostate-cancer-patients

TB disease mechanism and the molecule to block It - discovered ......

We know about the drug resistant tuberculosis and the havoc its causing, so there is an urgent need to  develop new drugs that can be useful. (have covered some articles on  drug development  for drug resistant TB in my earlier blogs). Many groups have tried to explain the resistance,  but now  researchers from Indiana University School of Medicine have identified a mechanism used by the tuberculosis bacterium to evade the body's immune system and have identified a compound that blocks the bacterium's ability to survive in the host, which could lead to new drugs to treat tuberculosis. 

The focus of the research was TB actions inside macrophages (infection fighting cells in the body's immune system). Macrophage cells' tools include the production of special proteins called cytokines to attack foreign invaders. Infected macrophages can also initiate a self-destruction mechanism called apoptosis, which signals other immune system cells to mount a defense against the infection. 

TB bacteria are able to disable the macrophage defenses by secreting virulent factors into the host. The IU team found that the actions of a particular virulent factor a protein phosphatase enzyme called mPTPB  blocked both the production of the infection-fighting cytokines, and the macrophage's self-destruct system. 

As for as my knowledge goes,  phosphatases  (VE-PTP, Cdc25A, PTP1b, VHR, Shp-2, MptpA und MptpB) the  key regulators of various life processes are being studied for the diverse activities. The following is the brief summary ;

a). VE-TPT inhibition is very promising in the development of antiangiogenesis inhibitors in cancer therapy.
b). Cdc25A influences cell cycle regulation and may also be a target of interest in cancer therapy.
c). The phosphatase MptpB, from Mycobacterium tuberculosis, influences the host's immune 
     reaction in a tuberculosis infection.
d) VHR dephosphorylates MAP kinases in the activation loop THX, which plays an important role in signal
    transduction processes.
e) Inhibiting MptpB and Shp-2 opens up new directions in the search for antibiotics and
f) The Ptp1B enzyme plays an important role in developing a medicine against type 2 diabetes and the
   metabolic syndrome.

Though many researchers  tried to study the mechanism of action by which the  tuberculosis bacterium is getting resistance,  this group has come up with a drug and this is of great significance in my opinion.

Using combinatorial chemical synthesis and high-throughput screening, (HTS) the researchers developed the I-A09 compound, which successfully blocked the action of mPTPB. Tests involving live TB bacteria were conducted at the Institute of Tuberculosis Research, University of Illinois at Chicago. 

As per the claim by the lead researcher, Dr. Zhong-Yin Zhang, compound I-A09 is being evaluated in a TB animal model at the Johns Hopkins University School of Public Health. More potent forms of the I-A09 compound are being pursued by the IU team for possible future clinical testing. Hope the team  will come up with a solution to this problem in the days to come...

Ref : http://www.medicine.indiana.edu/news_releases/viewRelease.php4?art=1232

Latrepirdine (dimbon) may ease cognitive effects of Huntington's disease....

We know that Dimebon (latrepirdine), an investigational drug currently in  Phase 3 development, that halt the onset of advanced Alzheimer’s (AD) and dramatically improve the quality of life for patients. Dimebon has a unique mechanism of action, distinct from currently available treatments. In preclinical studies, dimebon has been shown to protect brain cells from damage and enhance brain survival, potentially stabilising and improving mitochondrial function.

Now researchers from School of Medicine and Dentistry at the University of Rochester in New York lead by Dr. Karl Kieburtz, have found that  Dimebon may improve thinking, learning and memory skills in people with Huntington's disease  an inherited neurodegenerative disorder. 

Mitochondria are critical to brain cell functioning as they are the primary source of energy for cells. Drugs that protect mitochondria or restore their function could potentially be a valuable treatment approach in AD and Huntington's disease.

As per the claim by the researchers, the drug stabilizes and improves the function of mitochondria, parts of cells that help convert food into energy. Researchers found that, Dimebon (Latrepirdine)  at a dosage of 20 mg three times daily, is well-tolerated for 90 days in patients with Huntington's disease and may have a beneficial effect on cognition. Though further studies are essential to substantiate the claim, its good to see at l(e)ast a drug for Huntington's disease (the only approved therapy for Huntington's is tetrabenazine, which treats movement problems but does not prevent cognitive decline or change the course of the disease).....more...

FDA approves Olmesartan (Benicar, Olmetec) for children....

Olmesartan (Benicar, Olmetec-by Ranbaxy) is an angiotensin II  receptor antagonist used to treat high blood pressure. 

Mode of action : Olmesartan works by blocking the binding of angiotensin II to the AT₁ receptors in vascular muscle; it is therefore independent of angiotensin II synthesis pathways, unlike ACE inhibitors. By blocking binding rather than synthesis of angiotensin II, olmesartan inhibits the negative regulatory feedback on renin secretion. As a result of this blockage, olmesartan reduces vasoconstriction and the secretion of aldosterone. This lowers blood pressure by producing vasodilation, and decreasing peripheral resistance.

Now FDA has approved the hypertension treatment Benicar (olmesartan medoxomil) for use in children and adolescents 6 to 16 years of age.  Benicar was originally approved in 2002 for the treatment of hypertension in adults (Daiichi Sankyo, Inc.).

The approval of this expanded indication was based on a phase III study examining the antihypertensive effects of Benicar in pediatric patients. The study found Benicar to be safe and efficacious in children ages 6-16 with hypertension, resulting in blood pressure reductions that were statistically different in comparison to placebo. Benicar was generally well tolerated in pediatric patients, and the adverse event profile was similar to that for adults.

Ref : http://www.dsi.com/news/pdfs/FINAL_Benicar_Pediatric_Approval_Press_Release.pdf

Triapine with cisplatin a new standard of care for cervical cancer?

In continuation of my update on cancer drug development,   I found this  info interesting to share with. Researchers  lead by Dr. Charles Kunos at the Ireland Cancer Center of University Hospitals (UH)  have found that,  Triapine, (3-aminopyridine-2-carbox -aldehyde   thiosemicarbazone, see structure), which suppresses tumor growth shows a great deal of promise for cervical cancer patients who are at high risk for relapse and cancer-related death. 

The phase I study found that the chemotherapy medicine  Triapine, was well tolerated in combination with standard-of-care cisplatin chemotherapy and radiation treatment in women with cervical cancer. This regimen provided both significant reduction in cancer disease and cancer control.

In the study   (ten-patient study) patients,  were treated three times weekly with Triapine (a potent Ribonucleotide Reductase Inhibitor) in combination with weekly cisplatin treatment and daily pelvic radiation therapy over five weeks.  The researchers claims that  "a 100% complete response rate was observed and no disease progression was documented through 18 months of median follow-up."A phase two follow-up study is ongoing at the Ireland Cancer Center. UH Case Medical Center  Hope this new found combintaton will be  a promising new treatment to help women fight this aggressive disease in the days to come...

Ref : http://clincancerres.aacrjournals.org/content/16/4/1298.abstract?sid=f3df7c2d-9e46-4baf-b47b-83d310b87641

Enantioselective synthesis of Kinamycin F - a new hope for anticancer drug development ?

The kinamycins are a series of naturally occurring compounds endowed with intriguing molecular architectures and potent biological properties such as  antibiotic and antitumor activities. These novel diazofluorene-containing compounds defied chemical synthesis since their initial disclosure by Omura et al. in 1970 until the first total synthesis of kinamycin C by Porco et al. in late 2006.

Now, researchers from Yale University,  have  developed a new method to recreate this structure that allows them to synthesize the kinamycins with much greater efficiency than previously possible.

As per the claim by the researchers,  key to the success of the route was  the development of a three-step sequence for construction of the diazonapthoquinone (diazofluorene, blue in structure source : JACS) function of the natural product.

While scientists have produced kinamycins in the laboratory in the past, the Yale team was able to halve the number of steps required to go from simple, easily obtainable precursors to the complete molecule from 24 down to 12. 

This sequence comprises fluoride-mediated coupling of a β-(trimethylsilylmethyl)-cyclohexenone and halonapthoquinone, palladium-mediated cyclization to construct the tetracyclic scaffold of the natural product, and mild diazo-transfer to a complex cyclopentadiene to introduce the diazo function. Ortho-quinone methide intermediates, formed by reduction and loss of dinitrogen from (structure), have been postulated to form in vivo, and this approach provides a straightforward synthetic pathway to such compounds.

This research is of great importance because by shortening the synthesis one can now prepare these molecules in the quantities required for further studies, including animal studies and even clinical trials.

Working with researchers at the Yale School of Medicine and the Yale Chemical Genomics Screening Facility, the team has begun testing several of the compounds against cancer cells, with promising preliminary results. Next, they will work to understand the exact mechanism that makes the compounds,  which are benign on their own  highly toxic once they penetrate cells. Lead researcher Dr. Seth Herzon, says "the key to success will be whether they can develop selectivity - whether they can kill cancer cells in the presence of non-cancerous tissue". Dr.Herzon  is also optimistic about lomaiviticin A (which also has the reactive core kinamycin,  and is even more toxic and could prove even more effective in destroying cancer cells)...let us hope positive results from this study....

Ref : http://pubs.acs.org/doi/abs/10.1021/ja910769j 

Denosumab exhibits superiority over Zometa in treatment of prostate cancer men with bone metastases

Denosumab exhibits superiority over Zometa in treatment of prostate cancer men with bone metastases

Hyperthermia-free TRPV1 antagonists - new category of pain killers?

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1), also known as the capsaicin receptor is a protein which in humans is encoded by the TRPV1 gene. This protein is a member of the TRPV group of transient receptor potential family of ion channels. TRPV1 is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best known activators of TRPV1 are heat greater than 43°C,  pepper like chemicals  (capsaicin - most of us might have used gel containing capsaicin) and proton. The same channel is responsible for pain caused by these diverse stimuli. For a number of years scientists have focused on the development of TRPV1 antagonists, but have been stymied by the dangerous hyperthermia side effect.

Now researchers lead by  Dr. Andrej A. Romanovsky,  have come up with an explanation for the side effect and how one can avoid the side effect. 

Researchers found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (–0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). Hence they conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia. Researchers suggests that the  drugs that are being developed should be designed not to block the proton activation of TRPV1.

Scientists believe that this new generation of painkillers will be effective in treating pain related to a number of conditions including cancer, AIDS, migraines and diabetes. Let us hope some good news from these class of compounds....

Ref : Abstract of the paper