Navigation Links
Researchers find potential solution to melanoma's resistance to vemurafenib
Date:2/28/2012

TAMPA, Fla. -- Researchers at Moffitt Cancer Center in Tampa, Fla., and colleagues in California have found that the XL888 inhibitor can prevent resistance to the chemotherapy drug vemurafenib, commonly used for treating patients with melanoma.

Vemurafenib resistance is characterized by a diminished apoptosis (programmed cancer cell death) response. According to the researchers, the balance between apoptosis and cell survival is regulated by a family of proteins. The survival of melanoma cells is controlled, in part, by an anti-apoptotic protein (Mcl-1) that is regulated by a particular kind of inhibitor.

Their current findings, tested in six different models of vemurafenib resistance and in both test tube studies and in melanoma patients, demonstrated an induced apoptosis response and tumor regression when the XL888 inhibitor restored the effectiveness of vemurafenib.

The study appeared in a recent issue of Clinical Cancer Research, a publication of the American Association for Cancer Research.

"The impressive clinical response of melanoma patients to vemurafenib has been limited by drug resistance, a considerable challenge for which no management strategies previously existed," said study co-author Keiran S. M. Smalley, Ph.D., of Moffitt's departments of Molecular Oncology and Cutaneous Oncology. "However, we have demonstrated for the first time that the heat shock protein-90 (HSP90) inhibitor XL888 overcomes resistance through a number of mechanisms."

The diversity of resistance mechanism has been expected to complicate the design of future clinical trials to prevent or treat resistance to inhibitors such as vemurafenib.

"That expectation led us to hypothesize that inhibitor resistance might best be managed through broadly targeted strategies that inhibit multiple pathways simultaneously," explained Smalley.

The HSP90 family was known to maintain cancer cells by regulating cancer cells, making it a good target for treatment. According to the authors, the combination of vemurafenib and XL888 overcame vemurafenib resistance by targeting HSP90 through multiple signaling pathways.

There was already evidence that HSP90 inhibitors could overcome multiple drug chemotherapy resistance mechanisms in a number of cancers, including non-small lung cancer and breast cancer. Because XL888 is a novel, orally available inhibitor of HSP90, the researchers hoped that it would arrest the cancer cell cycle in melanoma cell lines.

In their study, the inhibition of HSP90 led to the degradation of the anti-apoptopiuc Mcl-1 protein. The responses to XL888 were characterized as "highly durable with no resistant colonies emerging following four weeks of continuous drug treatment." In other studies not using XL888, resistant colonies "emerged in every case," they reported.

"We have shown for the first time that all of the signaling proteins implicated in vemurafenib resistance are 'clients' of HSP90 and that inhibition of HSP90 can restore sensitivity to vemurafenib," concluded Smalley and his colleagues. "Our study provides the rationale for the dual targeting of HSP90 with XL888 and vemurafenib in treating melanoma patients in order to limit or prevent chemotherapy resistance."


'/>"/>
Contact: Ferdie De Vega
Ferdinand.DeVega@moffitt.org
813-745-7858
H. Lee Moffitt Cancer Center & Research Institute
Source:Eurekalert

Related medicine news :

1. Kessler Foundation researchers present at DC Conference on Race, Ethnicity and Disabilities
2. Researchers Spot Genes Behind Macular Degeneration
3. 90 percent of firefighters exhibit symptoms of PTSD according to Ben-Gurion University researchers
4. New blood test for early cancer detection developed by Ben-Gurion University researchers
5. UC Davis MIND Institute researchers to present on autism at AAAS Annual Meeting in Vancouver
6. Nasty superbug is being studied by UB researchers
7. Researchers see differences in Autism brain development as early as 6 months
8. As diabetes emerges, researchers track diseases first steps
9. Salk researchers find new drug target for lung cancer
10. GW researchers reveal digital transcriptome of breast cancer
11. PRP treatment aids healing of elbow injuries say researchers
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:12/4/2016)... ... December 03, 2016 , ... While James Earl Jones is known for myriad ... a show called "Front Page". One of the forthcoming episodes examines mammogram techniques; a ... plummeted in large part due to early detection. Like any other disease, treatments have ...
(Date:12/4/2016)... ... December 04, 2016 , ... Patients ... can now take advantage of a cosmetic procedure known as Carbon Dioxide ... reduces the appearance of age spots, fine lines, uneven coloration, wrinkles, scarring, ...
(Date:12/2/2016)... ... , ... Lori G. Cohen and Sara K. Thompson , ... American Conference Institute’s 21st Drug & Medical Device Litigation Conference , taking place ... conference. , Cohen, who chairs the firm’s Pharmaceutical, Medical Device & Health Care Litigation ...
(Date:12/2/2016)... AL (PRWEB) , ... December 02, 2016 , ... ... from across the Dothan-Wiregrass Area in Alabama are expected to attend the UNCF ... Schmitz, will help provide scholarship funds for area students and operating support to ...
(Date:12/2/2016)... ... ... The annual time frame to change Medicare health and prescription drug coverage, known ... Medicare beneficiaries who are looking to switch from their current plan to a Medicare ... during this period order for their new policy to go into effect in 2017. ...
Breaking Medicine News(10 mins):
(Date:12/2/2016)... , December 2, 2016 ... "In Vitro Diagnostics/IVD Market by Product (Instruments, Reagents, ... Application (Diabetes, Oncology, Cardiology, Nephrology, Infectious Diseases) - ... market is valued at USD 60.22 Billion in ... a CAGR of 5.5% during the forecast period ...
(Date:12/2/2016)... , December 2, 2016 ... Awards Committee honored excellence in research, development and innovation ... The gala dinner was held in the presence of ... the Russian Federation , Natalia Sanina, ... Mikhail Murashko , Head of Roszdravnadzor, National Service ...
(Date:12/2/2016)... RICHMOND, British Columbia , December 2, 2016 ... Produkt, den INSTI HIV-Selbsttest, bei den Mitgliedern des Apothekenbundes von Kenia eingeführt. ... ... INSTI HIV Self Test! (PRNewsFoto/bioLytical Laboratories) ...      (Photo: http://photos.prnewswire.com/prnh/20161201/444905 ) ...
Breaking Medicine Technology: