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Old 10-19-2013, 07:38 PM   #1
'lizbeth
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Post Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-resista

Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-resistant breast and gastric cancer.

Wainberg ZA, Anghel A, Rogers AM, Desai AJ, Kalous O, Conklin D, Ayala R, O'Brien NA, Quadt C, Akimov M, Slamon DJ, Finn RS.
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University of California Geffen School of Medicine, Department of Medicine, Division of Hematology/Oncology, Santa Monica, CA 90404, USA. zwainberg@mednet.ucla.edu

Abstract

HSP90 enables the activation of many client proteins of which the most clinically validated is HER2. NVP-AUY922, a potent HSP90 inhibitor, is currently in phase II clinical trials. To explore its potential clinical use in HER2-amplified breast and gastric cancers, we evaluated the effect of AUY922 alone and in combination with trastuzumab in both trastuzumab-sensitive and -resistant models. A panel of 16 human gastric and 45 breast cancer cell lines, including 16 HER2-amplified (3 and 13, respectively) cells, was treated with AUY922 over various concentrations. In both breast and gastric cancer, we used cell lines and xenograft models with conditioned trastuzumab-resistance to investigate the efficacy of AUY922 alongside trastuzumab. Effects of this combination on downstream markers were analyzed via Western blot analysis. AUY922 exhibited potent antiproliferative activity in the low nanomolar range (<40 nmol/L) for 59 of 61 cell lines. In both histologies, HER2-amplified cells expressed greater sensitivity to AUY than HER2-negative cells. In conditioned trastuzumab-resistant models, AUY922 showed a synergistic effect with trastuzumab. In vitro, the combination induced greater decreases in HER2, a G2 cell-cycle arrest, and increased apoptosis. In a trastuzumab-resistant gastric cancer xenograft model, the combination of AUY922 and trastuzumab showed greater antitumor efficacy than either drug alone. These data suggest that AUY922 in combination with trastuzumab has unique efficacy in trastuzumab-resistant models. The combination of HSP90 inhibition and direct HER2 blockade represents a novel approach to the treatment of HER2-amplified cancers and clinical trials based on the above data are ongoing.
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Old 10-19-2013, 07:42 PM   #2
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Re: Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-res

The above study is active, but not recruiting.
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Old 10-20-2013, 10:29 PM   #3
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Re: Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-res

I didnt research AUY922 (I will) but a former post mentioned Dacomitinib so I printed some articles on this investigational drug.

Dacomitinib is an interesting drug. It is a Tyrosine Kinase Inhibitor. Tyrosine is an amino acid with an OH group at its end. Its a derivative of Phenylalanine. When you start reading about investigational drugs you often will run into the words Tyrosine Kinase Inhibitor or TKI for short. I don't
want to get too chemical but when a PO4 or phosphate group
attaches onto the OH group of Tyrosine the cancerous gene becomes activated. Its like turning on the ignition of a car. The molecule ATP goes into a special "pocket" of
the molecule and provides the phosphate group that activates the cancer inducing protein. TKI drugs push the ATP molecule out of the "pocket." The first drug that did this well was Geevec (Imatinib) for Chronic Granulocytic Leukemia.

Dacomitinib is also a TKI. It inhibits the Epidermal Growth Factor Receptor (EGFR), the Her2 Neu protein receptor and the HER4 receptor (don't know about this one).

There were some studies in non small cell carcinoma of the lung. The dosage of Dacomitinib was 45mg daily. The main side effects were diarrhea, fatigue, mouth sores, mouth dryness, rash and acne like eruptions.

Paul
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Old 10-21-2013, 11:14 AM   #4
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Re: Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-res

Paul,

Thanks again for the explanation. I see many targeted therapies that are in early trials. They can't come soon enough for some of our stage IV ladies who could use some more treatment options.

I asked GDP, but I will ask you this too for more insight:

What affect does the supplement L-Tyrosine have on this cancer process?
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Old 10-21-2013, 09:51 PM   #5
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Re: Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-res

Elizabeth

Its an interesting question and I did some
very quick incomplete research while at work. The only cancer that
I can state for sure L-Tyrosine is contraindicated in is
Malignant Melanoma since Tyrosine is involved in Melanin
Synthesis. I cant say anything definitive about breast cancer yet, although there was a discussion among some
breast cancer patients who were using L Tyrosine (and
5-HT) for depressive symptoms. Ill do more extensive research over the weekend, but only melanoma stands out so far as a possible problem with L Tyrosine.

Paul
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Old 10-22-2013, 09:20 AM   #6
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Re: Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-res

I purchased some 5-HTP to help with memory, and my sister-in-law sent me 6 bottles of L-Tyrosine to help improve memory and attention.

I only take them once in a while, typically when I'm training and need to learn boatloads of information in a short time. My understanding is acetylcholine is the only neurotransmitter that you can supplement for - without developing decreased sensitivity to the supplements after 2 weeks.

I couldn't find any good information on the internet. GDP came up with the best answer in a prior post on the board.

I see discussion about Melanin and Vitamin D on wikipedia.
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Old 11-01-2013, 01:47 PM   #7
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Two HSP90 Cancer Trials Fall Short of Goal

Robert A. Nagourney, M.D.

Two related clinical trials were reported in the last several months describing the use of heat shock protein 90 (HSP90) inhibitors in lung cancer. Both trials fell short of their pre-specified endpoints casting a pall upon these drugs. However, the study of HSP90 inhibitors should not be abandoned based on these findings, as this is a fertile area of investigation and offers opportunities for the future.

Human cells marshal many defenses against stress. Thermal injury can damage basic cellular functions by denaturing (inactivating) proteins. The machinery of cells is largely comprised of protein enzymes. Excessive heat coagulates proteins much the same way the albumin of an egg turns white during cooking. The loss of fluidity and function ultimately results in cell death. The heat shock proteins come to the rescue by shepherding these proteins away from injury and protecting them from denaturation. There are many different heat shock proteins found in human cells, but one of the most abundant and active in cancer cells is known as HSP90 for its molecular weight in the range of 90-kilodaltons. Over the last two decades, investigators have explored the use of small molecules to inhibit these important proteins. Among the first compounds to be isolated and applied were derivatives of Geldanamycin. Although Geldanamycin itself is a poison that causes severe liver damage, its derivative 17-AAG, also known as Tanespimycin, has successfully entered clinical trials.

The current studies examined two other HSP90 inhibitors. One Retaspimycin, has been developed by the Infinity Pharmaceuticals. This clinical trial combined Retaspimycin with Docetaxel and compared results with Docetaxel alone in 226 patients with recurrent lung cancer. None of the patients had received Docetaxel prior to the trial. Drugs were administered every three weeks and the efficacy endpoint was survival with a subset analysis focused upon those with squamous cell cancer. The trial fell short of its pre-designated endpoint. Interestingly, the study failed to provide benefit even in patients who were specifically targeted by their tumor’s expression of the K-RAS, p53 or by elevated blood levels of HSP90, the putative biomarkers for response.

http://www.ncbi.nlm.nih.gov/pubmed/23580070

The second trial examined a different HSP90 inhibitor developed by Synta Pharmaceuticals. The drug Ganetespib was combined with Docetaxel and the combination was compared with Docetaxel alone. The results just reported indicate that the combination provided a median survival of 10.7 month, while Docetaxel alone provided a median survival of 7.4 month. Although this represented a three-month improvement, it did not meet the pre-specified target.

http://meetinglibrary.asco.org/content/112583-132

Taken together these results could dampen enthusiasm for these agents. This would be unfortunate, for this class of drugs is active in a number of human tumors.

Through our EVA-PCD functional profile we have observed favorable activity and synergy for the HSP90 inhibitor Geldanamycin and its derivative 17-AAG as we reported at the American Association for Cancer Research meeting in 2005 (Nagourney RA et al Proc. AACR, 2005). More importantly, 17-AAG (Tanespimycin) provided objective responses in 22 percent and clinical benefit in 59 percent of patients with recurrent HER2 positive breast cancer after these patients had failed therapy with Herceptin (Modi S. et al, Clinical Cancer Research August 2011). This clearly supports the role of HSP90 inhibition in breast cancer and would suggest that other more carefully selected target diseases could benefit as well.

The function of HSP90 is not completely understood as it influences the intracellular trafficking of dozens of proteins. One of the complexities of this class of drugs is that they protect and enhance the function of both good and bad proteins. After all, the HSP90 protein doesn’t know which proteins we as cancer doctors would like it to protect.

When we apply EVA-PCD analysis to these and other related classes of compounds, we focus our attention upon the downstream effects, namely the loss of cell survival. That is, whatever proteins are influenced, the important question remains “did that effect cause the cells to die?”

Classes of compounds with nonspecific targets like the HSP90 inhibitors will surely be the most difficult to characterize at a genomic or proteomic level: What protein? What gene? Functional platforms like the EVA-PCD offer unique opportunities to study these classes of agents. We are convinced that the HSP90 inhibitors have a role in cancer therapy. It would be unfortunate if these setbacks led us to “throw the baby out with the (hot) bathwater,” thus, slowing or preventing their use in cancer treatment.
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Old 11-01-2013, 01:49 PM   #8
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Heat-shock factor reveals its unique role in supporting highly malignant cancers

Whitehead Institute researchers have found that increased expression of a specific set of genes is strongly associated with metastasis and death in patients with breast, colon, and lung cancers. Not only could this finding help scientists identify a gene profile predictive of patient outcomes and response to treatment, it could also guide the development of therapeutics to target multiple cancer types.

The genes identified are activated by a transcription factor called heat-shock factor 1 (HSF1) as part of a transcriptional program distinct from HSF1's well-known role in mediating the response of normal cells to elevated temperature. In normal cells, a variety of stressors, including heat, hypoxia, and toxins, activate HSF1 leading to increased expression of so-called heat-shock or chaperone proteins that work to maintain protein homeostasis in stressed cells.

Scientists have known for some time that many cancer cells have higher levels of chaperones and that elevation of these proteins is important for survival and proliferation of tumor cells. Now, however, researchers in the lab of Whitehead Member Susan Lindquist report that HSF1 supports cancers not only by increasing chaperones, but by unexpectedly regulating a broad range of cellular functions that are important for the malignant behavior of tumor cells.

This activity allows for the development of the most aggressive forms of three of the most prevalent cancers, breast, lung, and colon. The findings, published this week in the journal Cell, build on earlier research from the Lindquist lab showing that elevated levels of HSF1 are associated with poorer prognosis in some forms of breast cancer. "This work shows that HSF1 is fundamentally important across a broad range of human cancers, cancers of various types from all over the body turn on this response," says Sandro Santagata, a postdoctoral researcher in the Lindquist lab. "That's very interesting. It suggests how important HSF1 must be for helping tumors become their very worst."

In addition to confirming that this gene activation program differs from that associated with heat shock, the researchers found that in many tumors, it becomes active in virtually all of the tumor's cells. "This demonstrates it isn't simply regions of microenvironmental stress within a tumor that drive HSF1 activity, but rather that HSF1 activation is wired into the core circuitry of cancer cells, orchestrating a distinct gene regulatory program that enables particularly aggressive phenotypes," says Marc Mendillo, a postdoctoral researcher in the Lindquist lab. "This suggests HSF1 itself could be a great therapeutic target."

Luke Whitesell, an oncologist and senior research scientist in the Lindquist lab, concurs that HSF1 is a conceptually appealing target for therapeutic intervention, noting that suppressing HSF1 for short periods of time should have minimal consequences on normal cells.

However, he adds, actually developing such a drug could be problematic. "Coming up with a drug that disrupts HSF1's interaction with DNA, which is how it activates all of these genes, that is going to be really tough," says Whitesell. "No one has come up with a clinically useful drug that directly interrupts a transcription factor's interaction with DNA yet. But there are ways to disrupt a transcription factor's function indirectly, as opposed to directly targeting the protein itself. What we have now from this research is a new view of the landscape and the possibilities for drug discovery and development that are out there."
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Old 11-01-2013, 06:22 PM   #9
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Re: Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-res

HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab.

Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, D'Andrea G, Dickler M, Moynahan ME, Sugarman S, Ma W, Patil S, Norton L, Hannah AL, Hudis C.
Source

Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. modis@mskcc.org

Abstract

PURPOSE:

HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.
EXPERIMENTAL DESIGN:

We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
RESULTS:

Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28).
CONCLUSIONS:

This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic intera
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Old 11-03-2013, 07:56 PM   #10
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Re: Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-res

Shanu Modi is my oncologist. I trust her implicitly. I considered this trial at one point but it was "new" for breast cancer at the time. Some great minds are associates on this endeavor. Thanks for posting.

Karen
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World Trade Center Survivor (56th Floor/North Tower): 14 years and still just like yesterday.
Graves Disease, became Euthyroid via Radioactive Iodine, June 2001.
Thyroid Eye Disease. 2003. Decompression surgery in 2009; eyelid lowering surgery in 2010.
Diagnosed: June 2010, liver mets. ER-/PR+10%; HER2+++.
July 2010: Begin Taxol/Herceptin. Eliminate sugar from diet. No surgery or radiation.
January 2011: NED
April 2011: Progression in liver only. Other previous affected areas eradicated. Stop Taxol/Herceptin after 32 infusions.
May 2011: Brain MRI: clear.
May 2011: Begin Tykerb daily, Xeloda twice per day for one week on, one week off, and Herceptin.
November 2011: Progression in liver. All other tumors remain eradicated.
December 2011: BEGIN TRIAL #09-093 Taxol, MCC-DM1 (T-DM1), Perjeta.
Trial requires scans every six weeks, bloodwork and infusions weekly.
Brain MRI: clear.
January 2012: NED. Liver mets, good riddance!
March 2012: NED. Developed SMA (rare blood clot) in intestinal artery and loss of sight in right eye due to optical nerve neuropathy. Resolved when Taxol removed this month.
Continue Protocol of T-DM1 weekly and Perjeta every 3 weeks.
May 2012: NED.
June 2012: Brain MRI: clear.
June-December 2012: NED.
December 2012: TRIAL CONCLUDED; ENTER TRIAL EXTENSION #09-037. CT, Brain MRI, bone scan: clear. NED.
January-March 2013: NED.
June 2013: Brain MRI: clear. CEA upticking; CT shows new met on liver.
July 3, 2013: DISASTER STRIKES during liver ablation: sloppy surgeon cuts intercostal artery and I bleed out, lose 3.5 liters of blood, have major hemothorax, and collapsed lung requiring emergency resuscitative thoracotomy, lung surgery, rib rearrangement and cutting deep connective tissue, transfusion. Ablation incomplete. This life-saving procedure would end up causing me unforgiving pain with every movement I make, permanently, otherwise known as forever.
July 26, 2013: Try Navelbine/Herceptin. Body too weak after surgery and transfusion. Fever. CEA: Normal.
August 16, 2016: second dose Navelbine/Herceptin; CEA: Normal. Will skip doses. Watching and waiting.
September 2013: NED, Herceptin only. CEA: Normal. Started Arimidex.
October-November 2013: NED. Herceptin and Arimidex. CEA, CA125, 15-3: Normal.
December 2013: Something brewing. PET lights up on little spot on liver; CEA upward trend, just outside normal. PET and triphasic liver scan confirm Little Met. Restart Perjeta with Herceptin, stay on Arimidex. Genomic sequencing completed for future treatments, if necessary.
January 2014: Ablate Little Met on the 6th. Happy New Year.
March 2014: Brain MRI: clear. PET/CT reveal liver mets return; new lung mets. This is not funny.
March 2014: BEGIN TRIAL #10-005 A(11)-Temsirolimus plus Neratinib.
April 2014: Genomic testing indicated they could work, they did not. Very strange drug combo for me, felt weird.
April 2014: Started Navelbine and Herceptin. Needed something tried and true, but had significant progression.
June 2014: Doxil and Herceptin.
July 2014: Progression. Got nothing out of it. Brain: NED.
July 2014: Add integrative medical hematologist-oncologist to my team. Begin supplements. These are tumor-busting, immune system boosters. Add glutathione, lysine and taurine IV infusions every three weeks.
July 2014: Begin Gemzar, Herceptin & Perjeta. Happy.
August 2014: ECHO perfect.
January 2015: Begin weekly Vitamin D Analog infusions. 25 mcg. via port.
February 2015: CT: stable.
April 2015: Gem working, but not 100%. Looking into immunotherapy. Finally, treatments for the 21st century!
April 2015: Penn Medicine. Dendritic cell immunotherapy.
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