Exelixis, Inc. Message Board

I'm glad someone found XL888 is still being studied.I remember working on this from the early to mid 2000's period.And how there was excitement and great hope for XL888.

Inhibitor XL888 found to restore chemotherapy sensitivity
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."

"this drug isn't even in Phase I human trials and probably won't be relevant until later in the decade barring an FDA break-through designation surprise." Thanks that reaffirms my thought it wasn't going to have much impact on Cabo.

Sometimes it's pure speculation and nothing more.Some do take gambles.

I searched the entire Takeda Clinical Study Protocol Summaries and other places on the Takeda website and can't find T-1840383?

Molecular Cancer Therapeutics shows the chemical structure of T 1840383.Under A Novel Inhibitor of c-Met and VEGF Receptor Tyrosine Kinases with a Broad Spectrum of In Vivo Antitumor Activities
•Supplementary Figure 1 - PDF File - 52K, Chemical structure of T-1840383 and other VEGFR or c-Met selective inhibitors.

Takeda Pharmaceutical Company Limited they once were talking to them for an Asian market connection.If I remember correctly.

PubMed also has some more info. on T-1840383.

Although they eliminated most of the research team: if there is a home run hit from whats being tested now, couldn't that fill the coffers? And since Exel has an enormous library of information wouldn't it be likely they would then add more R&D postions?

Thanks. I put that in a search and it said couldn't be found? But I have it on screen mow. Interesting stuff.

? What I found was the following:"Home
XL888
Developed and owned by Exelixis $EXEL. Efforts on this projects, along with other drugs at EXEL, was halted when the company decided to focus exclusively on cabozantinib (XL184). Prior to this re-prioritization, this asset

"XL888 is an orally available small molecule inhibitor of HSP90, a chaperone protein that promotes the activity and stability of a range of client proteins, including kinases, which play key regulatory roles in cells. The activity of HSP90 is particularly prominent in tumor cells, where it promotes the activity of proteins controlling proliferation and survival. XL888 is a potent and selective ATP-competitive inhibitor of HSP90, and binds to its target in a manner that is structurally distinct from other HSP90 inhibitors currently in the clinic."

"XL888 is being evaluated in a phase 1 trial in patients with solid tumors. This trial was initiated based on a substantial body of preclinical data demonstrating that XL888 induces marked degradation of HSP90 client proteins and inhibits the proliferation of a broad panel of human tumor cell lines that are dependent on client proteins. XL888 is highly active in multiple human tumor xenograft models and has a favorable pharmacokinetic profile. The preclinical activity profile of XL888 is highly supportive of its clinical development for the treatment of cancers that are driven by proteins regulated by HSP90."
Clinical Trials
Phase 1 Study in patients with solid tumors (NCT00796484) - This study commenced in November 2008 but was terminated by the company in April 2011."

Did they all actually buy the shares 5/23/13? Or are they just exercising Options granted at an earlier date?According to that site;it says,Date Exercisable Expiration Date 5/23/2013, Expiration Date 5/22/2020.Now I had Options I exercised a long time ago but they cost a fraction of current value at the time.It wasn't the same as buying the shares on the open market.

I went too Sec Filings Insider Trading - Exelixis Inc. (EXEL) SEC Form 4 and don't see that stated? Where did ytou come up with your facts? What I find is :Transaction
& Date Reported
Date Company Symbol Insider
Relationship Shares
Traded Average
Price Total
Amount Shares
Ownership Filing
2013-05-15
Exercise
Tax Withholding 2013-05-17
7:21 pm EXELIXIS, INC. EXEL MORRISSEY MICHAEL
(President and CEO
Director) 4,302 $0 $0 3,640
(Direct) View
2013-05-15
Exercise
Tax Withholding 2013-05-17
7:17 pm EXELIXIS, INC. EXEL Schwab Gisela
(EVP and Chief Medical Officer) 3,011 $0 $0 64,603
(Direct) View
2013-05-15
Exercise
Tax Withholding 2013-05-17
7:17 pm EXELIXIS, INC. EXEL Lamb Peter
(EVP, Discovery Research & CSO) 4,300 $0 $0 28,194
(Direct) View
2013-05-15
Exercise
Tax Withholding 2013-05-17
7:17 pm EXELIXIS, INC. EXEL KARBE FRANK
(EVP and CFO) 2,688 $0 $0 89,295
(Direct) View
2013-05-15
Exercise
Tax Withholding 2013-05-17
7:16 pm EXELIXIS, INC. EXEL SIMONTON PAMELA A
(EVP and General Counsel) 2,581 $0 $0 14,797
(Direct) View
2013-02-15
Exercise
Tax Withholding 2013-02-15
8:35 pm EXELIXIS, INC. EXEL Schwab Gisela
(EVP and Chief Medical Officer) 3,213 $0 $0 58,037
(Direct) View
2013-02-15
Exercise
Tax Withholding 2013-02-15
8:35 pm EXELIXIS, INC. EXEL SIMONTON PAMELA A
(EVP and General Counsel) 2,754 $0 $0 13,628
(Direct) View
2013-02-15
Exercise
Tax Withholding 2013-02-15
8:34 pm EXELIXIS, INC. EXEL Lamb Peter
(EVP, Discovery Research & CSO) 4,590 $0 $0 26,246
(Direct) View
2013-02-11-
-2013-02-15
Exercise
Gift
Tax Withholding 2013-02-15
8:34 pm EXELIXIS, INC. EXEL MORRISSEY MICHAEL
(President and CEO
Director) 8,516 $0 $0 1,692
(Direct
Indirect) View
2013-02-15
Exercise
Tax Withholding 2013-02-15
8:33 pm EXELIXIS, INC. EXEL KARBE FRANK
(EVP and CFO) 2,868 $0 $0 81,789

Your superiority trait is very abrasive.Continually posting your thoughts of what one should and should not do is so overbearingly.You are just simply rude.There's one way to stop you. Your now on ignore.

It's the most common type of bladder cancer. About 60,000 American per/yr. develope it.

Should have happened this morning: •Abstract TPS4589: “A phase II study of cabozantinib (XL184) in patients with advanced/metastatic urothelial carcinoma.”
[Note: This is a study conducted by the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP).]

Dr. Andrea Apolo, Center for Cancer Research, National Cancer Institute, Bethesda, MD
General Poster Session: Genitourinary (Nonprostate) Cancer (Trials in Progress subsession)
Monday, June 3, 8:00-11:45 a.m., S Hall A2

$49.25

I doubt there will be any surprises. I just think they are extremely cautious and very moderate. Another thing I asked about at the A.S.H.M. was dilution. I told them I was very unhappy with the share value and all the dilution. Frank Karbe told me going forward they were fine and not to look for anymore in the near future. I wonder what near is to him? They all gave me the picture of confidence about Cabo and it becoming a franchise with merit and value. Was it a smoke screen? I sure don't know. i only keep my fingers crossed.

No I'm sorry she didn't.

Actually I'm still waiting for my 401K Exel shares to either reach the stratosphere and I sell the Exel shares.Which means I no longer can keep the other money in the 401K.I'd prefer to keep the money in the 401K and not roll the money to an IRA.But the rotten laws don't allow that.Or the share price falls into an abyss.I have waited now almost 16 yrs..At Exelixis the one quality I was most noted for is my tremendous discipline.Gd. luck zjitters!