View Full Version : flu vaccination in breast cancer patients
ABSTRACT: Influenza vaccination in patients with breast cancer: A case-series analysis [Medical Science Monitor; Subscribe]
Background: Our aim was to evaluate the serological response and safety of influenza vaccine in patients with breast cancer in Mexico.
Material/Methods: Between October and December 2001, patients with breast cancer were vaccinated with a split virus vaccine. Hemagglutination inhibition assay titers were measured before vaccination and 4-6 weeks later. Titer ratios were used as the primary measure of response. When comparing rate of response according to treatment, stage, or other patient-related variables, individuals with post vaccination titers ?1:40 for all 3 antigen strains were called respondents.
Results: We analyzed 146 patients who were vaccinated and had influenza antibodies measured before and after vaccination. Seventy-two (49.3%) had locally advanced breast cancer, 117 (80.1%) were receiving cancer treatment, 91 (62.3%) were on chemotherapy. Response to vaccine was 47.2%; we found an additional 25.3% of patients who responded to two of the serotypes. In patients receiving chemotherapy the response rate was lower (p=NS).
Conclusions: The results of the present study show that influenza vaccine is safe and well tolerated in patients with breast cancer, but we observed a lessening of the immune response among patients receiving chemotherapy. Influenza vaccination should be recommended in all patients with breast cancer, regardless of the anti-neoplasic treatment.
StephN
10-04-2006, 11:58 AM
For the reminder.
I am just about to go out for my visit with my new oncologist, and will add the flu shot to the list of things to discuss or ask for. Maybe she would have brought it up, but now I won't forget for sure!
I get a flu shot at the cancer center each year, and have had nothing more than a little cold in the winters.
On course being careful to stay away from people in stores or other public places who are coughing, sneezing or otherwise look unwell is always helpful.
rinaina
10-04-2006, 12:35 PM
Funny this post appears now, I just put a call into my onc to ask if it is ok that I get a flu shot and they said next time I am in they will give me one. Guess it is okay.
Yeap. It's October and I have it in list to ask at my next visit as well. I got it last year and it worked but I think it helped more to stay away from public places with a lot of crowds and wash, wash, wash hands.
XOXO
MCS ( maria)
Lani. Have stage 2 went to stage 4 triple neg friend. What can she do? She's a pharmacist so I guess she has some clue. Help me help her. BB
see if your friend can have her slides sent to MD Anderson for a second pathologic opinion. They look for EGFR1 in triple negatives, making treatment with IRESSA/TARCEVA/ ERBITUX / and perhaps Tykerb in a clinical trial. In a minute I will add the latest article I found on triple negative breast cancer --just published a few days ago. It is somewhat difficult as they have fewer targets identified for treatment, although they respond better to chemotherapy than ER+ breast cancer.
Am currently packing to leave Denmark on Tuesday. If you repost your question to me a week from Sunday(allowing me time to recover somewhat from jetlag), I will be happy to do a more extensive search of the literature. I will also go through my email sent to the husband of a triple negative bc patient and forward the pertinent ones via this website to you.
Off to retrieve the recent article PS it is also referred to as basal-type breast cancer.
way around it?
1: Trends Mol Med. 2006 Sep 28; [Epub ahead of print] Links
Deconstructing the molecular portrait of basal-like breast cancer.
Yehiely F,
Moyano JV,
Evans JR,
Nielsen TO,
Cryns VL.
Cell Death Regulation Laboratory, Departments of Medicine and Cell and Molecular Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Gene-expression profiling has revealed several molecular subtypes of breast cancer, which differ in their pathobiology and clinical outcomes. Basal-like tumors are a newly recognized subtype of breast cancer, which express genes that are characteristic of basal epithelial cells, such as the basal cytokeratins, and are associated with poor relapse-free and overall survival. However, the genetic and epigenetic alterations that are responsible for the biologically aggressive phenotype of these estrogen receptor-negative and HER2/ErbB2-negative tumors are not well understood, thereby hindering efforts to develop targeted therapies. Here, we focus on new insights into the molecular pathogenesis of basal-like breast cancer and explore how these discoveries might impact the treatment of these poor-prognosis tumors.
CLTann
10-06-2006, 01:35 PM
Regarding flu vaccination, the success rate is totally overblown. Only several strains of flu are in the vaccine. The pharmaceutical companies took a guess on which flu MAY occur the coming season. If they guessed wrong, the flu shots are useless. Stay away from sick people is the primary good practice for all people. Moreover, the side effects of vaccine are quite severe for some people. In fact, many come down with flu after vaccination. My family never took flu vaccination.
Ann
Thanks Lani. I'll see if I can get into the article myself. I'll post next week. Sorry guys for getting off topic. I have been getting flu shots to protect my son with asthma. Haven't had the flu in many years. BB
sassy
10-06-2006, 07:12 PM
Went for treatment yesterday and they walked in with my flu shot. Last year (after bc) was the first time I had ever had a flu shot. Never had the flu either!
________
PussyCat_ (http://camslivesexy.com/cam/PussyCat_)
sarah
10-07-2006, 02:01 AM
When I was in chemo I asked the doctors at the hospital in France about the flu vaccine and they said yes get one, your immune system is down and it would not be good to get the flu.
One year many years ago before I had cancer, I got the flu and I was very sick for nearly a week and so weak I decided after that to always get one unless it was not advised for some reason. My husband and I will get one shortly.
Of course if they pick the wrong flu, it's useless and staying away from sick people is a good idea but not easy! of course during chemo it is especially important.
sarah
a couple of articles on triple negative bc hot off the press--as I awake I will try to post more to your attention:
ABSTRACT: Metaplastic breast carcinomas are basal-like tumours [Histopathology]
Aims: Recently, an immunohistochemical panel comprising antibodies against HER2, oestrogen receptor (ER), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6 was reported to identify basal-like breast carcinomas, as defined by cDNA microarrays. Our aim was to analyse a series of metaplastic breast carcinomas (MBCs) using this panel plus two other basal markers (CK14 and p63) and progesterone receptor (PR), to define how frequently MBCs show a basal-like immunophenotype.
Methods and results: Sixty-five cases were retrieved from the pathology archives of the authors' institutions and reviewed by three of the authors. Immunohistochemistry with antibodies for HER2, ER, EGFR, CK5/6, CK14 and p63 was performed according to standard methods. All but six cases (91%) showed the typical immunoprofile of basal-like tumours (ER- and HER2-, EGFR+ and/or CK5/6+). When CK14 and p63 were added to the panel, two additional cases could be classified as basal-like. The majority of MBCs lacked PR, except 4/19 (21%) carcinomas with squamous metaplasia.
Conclusions: Our results demonstrate that MBCs show a basal-like phenotype, regardless of the type of metaplastic elements. Moreover, as these neoplasms frequently overexpress EGFR (57%), patients with MBC may benefit from treatment with anti-EGFR drugs.
ABSTRACT: Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast [Histopathology]
Aims: Cytokeratin (CK) 14, a myoepithelial marker, is also expressed in a proportion of breast carcinomas. There is evidence that these tumours show a differing metastatic pattern and clinical outcome from other invasive ductal carcinomas (IDCs) and may need different management. Currently, they are not identified in routine practice and no morphological guidelines exist to aid their identification. The aim of this study was to analyse the histological features of CK14+ IDC.
Methods and results: A detailed histological review of 453 grade 3 IDCs revealed 88 (19.4%) that expressed CK14. Assessment was made independently by two pathologists using a standardized 'tick-box' proforma covering grade, architectural and cytological features. The results were analysed using logistic regression to identify features that predicted for basal phenotype. Concordance between the two pathologists was fair to good for most parameters (? 0.4-0.6). On multiple logistic regression, the basal phenotype was highly significantly associated with the presence of a central scar (P = 0.005), tumour necrosis (P < 0.0001), presence of spindle cells (P = 0.006) or squamous metaplasia (P < 0.0001), high total mitotic count (> 40 per 10 high-power field) (P = 0.0002) and high nuclear-cytoplasmic ratio (P = 0.0002).
Conclusions: Specific morphological features are strongly associated with basal-like breast carcinoma. These could be used in routine diagnostic practice to identify this important subset of tumours.
Try to get her tumor EGFR tested by Targeted Molecular Diagnostics. You did not say what stage she is--that may influence whether she can find someone to give her tarceva/iressa/erbitux/tykerb(lapatinib) in a trial or off-label
if her tumor is EGFR + the "cauliflower,brussel sprout, cabbage, broccoli"compound I3C may be helpful:
Links
EGFR and Src are involved in indole-3-carbinol-induced death and cell cycle arrest of human breast cancer cells.
Moiseeva EP,
Heukers R,
Manson MM.
Cancer Biomarkers and Prevention Group, Departments of Biochemistry and Cancer Studies, University of Leicester, Leicester LE1 7RH, UK.
Indole-3-carbinol (I3C), a dietary chemopreventive compound, induced marked reduction in EGFR prior to cell death in cells representing three breast cancer subtypes. Signaling pathways, linking these events were investigated in detail. I3C modulated tyrosine phosphorylation from 30 min in four cell lines. In MDA-MB-468 and HBL100 cells, it induced Src activation after 5 h. In MDA-MB-468 cells, I3C-induced signaling between 4.5 and 7 h, which involved sequential activation of Src, EGFR, STAT-1 and STAT-3, followed by EGFR degradation. It also induced physical association between activated Src and EGFR. In MCF7 and MDA-MB-231 cells, I3C modulated expression of cell cycle-related proteins, p21Cip1, p27Kip1, cyclin E, cyclin D1 and CDK6, with upregulation of p21Cip1 and cyclin E being dependent on Src. Inhibition of EGFR by specific inhibitors PD153035 or ZD1839 increased susceptibility to I3C-induced apoptosis of MCF7, MDA-MB-468 and MDA-MB-231 cells. Inhibition of Src sensitized MDA-MB-468 and MDA-MB-231 cells to I3C, whereas overexpression of c-Src increased resistance to I3C in MDA-MB-468 and HBL100 cells. Modulation of Src in MDA-MB-468 cells influenced the basal level of EGFR expression and cell viability; the latter being positively correlated with EGFR activation levels. Therefore, EGFR and Src activities are essential for I3C-induced cell cycle arrest and death; however, I3C-induced pathways depend on specific features of breast cancer cells. The cancer types, which rely on "EGFR addiction" or Src deregulation, are likely to be susceptible to I3C.
PMID: 16956907 [PubMed - as supplied by publisher]
for the future--
1: Br J Cancer. 2006 Sep 4;95(5):616-26. Epub 2006 Aug 1. Links
Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours.
Skliris GP,
Leygue E,
Curtis-Snell L,
Watson PH,
Murphy LC.
Department of Biochemistry & Medical Genetics, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada R3E OV9.
To analyse the phenotype of breast tumours that express oestrogen receptor-beta (ERbeta) alone tissue microarrays were used to investigate if ERbeta isoforms are associated with specific prognostic markers and gene expression phenotypes in ERalpha-negative tumours. ERalpha-negative tumours were positive for ERbeta1 in 58% of cases (n=122/210), total ERbeta in 60% (n=115/192) and ERbeta2/cx in 57% of cases (n=114/199). Oestrogen receptor-beta1 and total ERbeta were significantly correlated with Ki67 (r=0.28, P<0.0001, n=209; r=0.29, P<0.0001, n=191) and with CK5/6, a marker of the basal phenotype (r=0.20, P=0.0106, n=170; r=0.18, P=0.0223, n=158). ERbeta2/cx was strongly associated with p-c-Jun and NF-kappaBp65 (r=0.53, P<0.0001, n=93; r=0.35, P<0.0001, n=176). This study shows that a range of ERbeta isoform expression occurs in ERalpha-negative breast tumours. While expression of ERbeta1, total and ERbeta2/cx are correlated, individual forms show associations with certain phenotypes that suggest different roles in subsets of ERalpha-negative cancers. Based on our in vivo observations, ERbeta may have the potential to become a therapeutic target in the specific subcohort of ERalpha-negative breast cancers.
PMID: 16880783 [PubMed - indexed for MEDL
ie, if/when they test an agent (monoclonal antibody, false ligand, etc ) against ER beta, it might be useful in some cases of triple negative bc
TMD can also test for VEGFR--perhaps she could find a trial for Avastin or avastin plus an anti-EGFR tyrosine kinase inhibitor or monoclonal antibody:
Am J Clin Pathol. 2006 Apr;125(4):512-8. Links
Vascular endothelial growth factor expression in the basal subtype of breast carcinoma.
Ribeiro-Silva A,
Ribeiro do Vale F,
Zucoloto S.
Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
The recognition of subtypes of breast carcinomas based on their molecular features has brought new perspectives in breast cancer research. Some key regulators of angiogenesis and tumor infiltration were evaluated in breast carcinomas of basal phenotype (cytokeratin [CK]5+). Immunohistochemical analysis with 14 primary antibodies was performed in 100 formalin-fixed, paraffin-embedded samples of invasive ductal carcinomas. CK5 correlated with indicators of poor outcome, including precocious age, high histologic grade, lymph node positivity, advanced pathologic stage, negativity for hormonal receptors, and a high proliferative rate (Ki-67 labeling index). CK5 also correlated with vascular endothelial growth factor (VEGF) expression but not with the microvessel density. Considering that VEGF-overexpressing neoplastic mammary cells display increased proliferative activity in vitro regardless of the angiogenic effect of VEGF, the differential expression of VEGF might contribute to the more aggressive behavior of these neoplasms. CK5 correlated with tissue inhibitor of metalloproteinase (TIMP)-1, but not matrix metalloproteinase (MMP)-1, MMP-2, extracellular matrix metalloproteinase inducer, TIMP-2 or plasminogen activator inhibitor, indicating that antiproteolytic stimuli might be preponderant in these neoplasms.
PMID: 16627261 [PubMed - indexed for MEDLINE]
need for new approach--
J Clin Pathol. 2006 Jul;59(7):729-35. Epub 2006 Mar 23. Links
Basal-like breast carcinomas: clinical outcome and response to chemotherapy.
Banerjee S,
Reis-Filho JS,
Ashley S,
Steele D,
Ashworth A,
Lakhani SR,
Smith IE.
Breast Unit, Royal Marsden Hospital, London, UK.
BACKGROUND: Grade-III invasive ductal carcinomas of no special type (IDCs-NST) constitute a heterogeneous group of tumours with different clinical behaviour and response to chemotherapy. As many as 25% of all grade-III IDCs-NST are known to harbour a basal-like phenotype, as defined by gene expression profiling or immunohistochemistry for basal cytokeratins. Patients with basal-like breast carcinomas (BLBC) are reported to have a shorter disease-free and overall survival. MATERIAL AND METHODS: A retrospective analysis of 49 patients with BLBC (as defined by basal cytokeratin expression) and 49 controls matched for age, nodal status and grade was carried out. Histological features, immunohistochemical findings for oestrogen receptor (ER), progesterone receptor (PgR) and HER2, and clinical outcome and survival after adjuvant chemotherapy were compared between the two groups. RESULTS: It was more likely for patients with BLBCs to be found negative for ER (p<0.0001), PgR (p<0.0001) and HER2 (p<0.01) than controls. Patients with BLBCs were found to have a significantly higher recurrence rate (p<0.05) and were associated with significantly shorter disease-free and overall survival (both p<0.05). In the group of patients who received anthracycline-based adjuvant chemotherapy (BLBC group, n = 47; controls, n = 49), both disease-free and overall survival were found to be significantly shorter in the BLBC group (p<0.05). CONCLUSIONS: BLBCs are a distinct clinical and pathological entity, characterised by high nuclear grade, lack of hormone receptors and HER2 expression and a more aggressive clinical course. Standard adjuvant chemotherapy seems to be less effective in these tumours and new therapeutic approaches are indicated.
PMID: 16556664 [PubMed - indexed for MEDLINE]
J Cell Biochem. 2006 May 1;98(1):221-33. Links
Targeting the NF-kappaB pathway in estrogen receptor negative MDA-MB-231 breast cancer cells using small inhibitory RNAs.
Monks NR,
Pardee AB.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cancer cells in order to survive are often mutated to block apoptosis. One chemotherapeutic option is the re-establishment of apoptosis. An example of such a therapy is the PKC inhibitor Go6976, which activates apoptosis and shrinks in vivo tumors in estrogen receptor-negative breast cancers. We proposed as a mechanism blockage of activation of the transcription factor NF-kappaB, which is anti-apoptotic and often elevated in cancers. Over recent years, questions have arisen regarding the specificity of these "small-molecule inhibitors." We have therefore explored the role of NF-kappaB inhibition in MDA-MB-231 breast cancer cells using small inhibitory RNAs (siRNA). siRNAs designed against NF-kappaB protein p65 (RelA) and IKKalpha, IKKbeta, and IKKgamma, strongly decreased the target proteins. But, unlike Go6976, they did not decrease basal NF-kappaB or cause apoptosis. In particular, the decrease in p65 protein had no effects on apoptosis or cell proliferation, thus questioning the importance of NF-kappaB alone in the maintenance of these cells. Furthermore, the proteasome inhibitor MG-132 caused loss of IkappaBalpha, and an increase of it is phosphorylated form, but basal NF-kappaB was unchanged, whilst activation of NF-kappaB by TNFalpha was completely inhibited, suggesting that MG-132 activity is independent of constitutive NF-kappaB activation. We ascribe these differences to the specificity of inhibition by siRNAs as compared to the well-known non-specificity of small-molecule inhibitors. We conclude that the mutations in these cancer cells made them resistant to apoptosis, by elevating their NF-kappaB and activating other basal pathways that are blocked by Go6976 but not by IKK and p65 siRNAs.
PMID: 16408291 [PubMed - in process]
Links
Zoledronic-acid-induced circulating level modifications of angiogenic factors, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients.
Ferretti G,
Fabi A,
Carlini P,
Papaldo P,
Cordiali Fei P,
Di Cosimo S,
Salesi N,
Giannarelli D,
Alimonti A,
Di Cocco B,
D'Agosto G,
Bordignon V,
Trento E,
Cognetti F.
Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy. gia.fer@flashnet.it
BACKGROUND: To evaluate the modifications of circulating angiogenic factors, metalloproteinases and acute-phase cytokines after the first single zoledronic acid (ZA) intravenous infusion. EXPERIMENTAL DESIGN: Eighteen consecutive breast cancer patients with bone metastases were evaluated for circulating levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), metalloproteinase 1 (MMP-1), metalloproteinase 2 (MMP-2), interleukins 1beta, 6 and 8 (IL-1beta, IL-6, IL-8), interferon gamma, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta1 just before and 2 and 7 days after ZA infusion. RESULTS: The MMP-2 basal value showed a statistically significant decrease 48 h after ZA (p = 0.01), being at 7 days higher than the day 2 value (p = 0.03). The VEGF basal value showed a statistically significant decrease 48 h after ZA infusion (p = 0.03), increasing above the basal level at 7 days (p = 0.07). The bFGF basal level almost significantly decreased 2 days after infusion (p = 0.06), being at 7 days higher than the basal value (p = 0.09). Comparing the day 2 values with basal ones, the linear regression model showed a significant positive correlation between IL-8 and bFGF (p = 0.02), IL-8 and TNF-alpha (p < 0.0001), bFGF and TNF-alpha (p = 0.01), MMP-1 and TNF-alpha (p = 0.02). CONCLUSIONS: ZA could exert an antiangiogenic activity and inhibition of tumor cell bone invasiveness by a transient reduction of VEGF, bFGF and MMP-2 circulating levels after infusion.
PMID: 16088233 [PubMed - indexed for MEDLINE]
Clin Cancer Res. 2005 Aug 15;11(16):5678-85. Links
Breast cancer molecular subtypes respond differently to preoperative chemotherapy.
Rouzier R,
Perou CM,
Symmans WF,
Ibrahim N,
Cristofanilli M,
Anderson K,
Hess KR,
Stec J,
Ayers M,
Wagner P,
Morandi P,
Fan C,
Rabiul I,
Ross JS,
Hortobagyi GN,
Pusztai L.
Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
PURPOSE: Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like, normal-like, and erbB2+ subgroups were identified and were shown to have different prognoses. The goal of this research was to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy. EXPERIMENTAL DESIGN: Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the previously reported "breast intrinsic" gene set was used for hierarchical clustering and multidimensional scaling to assign molecular class. RESULTS: The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% [95% confidence interval (95% CI), 24-68] and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade. None of the 61 genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+ group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor-negative subtypes. CONCLUSIONS: The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers.
PMID: 16115903 [PubMed - indexed for MEDLINE]
recent article on curcumin mechanism of action--not ER or her2 dependent mechanism of action, so perhaps....?
1: Carcinogenesis. 2006 Oct;27(10):2008-17. Epub 2006 Apr 12. Links
Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through CHOP-independent DR5 upregulation.
Jung EM,
Park JW,
Choi KS,
Park JW,
Lee HI,
Lee KS,
Kwon TK.
Department of Immunology, School of Medicine, Keimyung University 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.
Death receptor DR5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we showed that curcumin, a plant product containing the phenolic phytochemical, is a potent enhancer of TRAIL-induced apoptosis through upregulation of DR5 expression. Both treatment with DR5/Fc chimeric protein and silencing of DR5 expression using small interfering RNA (siRNA) attenuated curcumin plus TRAIL-induced apoptosis, showing that the critical role of DR5 in this cell death. Curcumin also induced the expression of a potential pro-apoptotic gene, C/EBP homologous protein (CHOP), both at its mRNA and protein levels. However, suppression of CHOP expression by small interfering RNA did not abrogate the curcumin-mediated induction of DR5 and the cell death induced by curcumin plus TRAIL, demonstrating that CHOP is not involved in curcumin-induced DR5 upregulation. Taken together, the present study demonstrates that curcumin enhances TRAIL-induced apoptosis by CHOP-independent upregulation of DR5.
PMID: 16613838 [PubMed - in process]
again I am assuming your friend does not have early breast cancer, but rather metastatic breast cancer, so that it is more likely they might try something unusual...
Dr Neil Rosen of Memorial Sloane Kettering is working on 17 AAG Here is some info:
A Multipronged Attack on the Cancer Cell
Mr. Protein Head?
For most of its serious chaperoning, HSP90 functions as part of so-called super-chaperone complexes of HSPs. In fact, HSP90 actually directs their formation. "It's like a Mr. Potato Head," Dr. Neckers says. "It serves as an assembling point for other chaperone proteins."
These HSP complexes lie at the center of 1 theory behind the fact that 17-AAG has at least 20 times more affinity for HSP90 in cancer cells than it does in normal cells. Nobody has proven why this occurs, but the theory holds that in a normal cell, HSP90 is relatively dormant because there is little stress for it to react to. But as Dr. Whitesell explains, "Cancer cells, unlike normal cells, are already at their margin in utilizing their full HSP90 capacity…so it's highly activated and more sensitive to the drug."
The cancer cell differs from a normal cell in several ways. One big difference is that a cancer cell can survive, and in some cases thrive, under environmental assaults - such as the severe lack of oxygen in tumors or even the onslaught of cytotoxic chemotherapy agents - that would destroy a normal cell.
These remarkable survival skills are due in no small part to a family of proteins spurred to action by stress in the cellular environment. These so-called heat shock proteins (HSPs) serve as both molecular mechanics and bodyguards to other proteins. Stressed intracellular proteins that begin to misfold, for instance, are quickly repaired. Mutated proteins that otherwise would be shuttled away by the cell for degradation are somehow aided in carrying out their tasks as transcription factors, hormone receptors, and the like.
One HSP in particular, HSP90, has fascinated researchers because many of its "client" proteins - those that require HSP90's chaperoning skills in both normal and stress-laden environments - also are members of the most-wanted list of proteins that spur cancer development and growth, including mutant p53, Bcr-Abl, HER-2, HIF-1, and many others.
Therein lies HSP90's potentially immense therapeutic value, says Dr. Len Neckers, a senior principal investigator in NCI's Urologic Oncology Branch, who has been a leader in HSP90 research.
"By inhibiting HSP90, you avoid focusing on a specific step in cancer development, which, as we're beginning to see, tends to allow cancers to evade molecularly targeted attacks," he says. "By inhibiting HSP90, we're simultaneously attacking multiple signaling nodes of a cancer cell's survival network."
In 1993, Dr. Neckers and his NCI colleagues discovered that a common, off-patent antibiotic, geldanamycin, could inhibit HSP90's chaperoning function. It was the first such discovery, and it launched an onslaught of research at institutions across the country and the world to delve deeper into HSPs in terms of their functionality and anticancer potential.
Jump ahead more than a decade, and five phase I trials testing a geldanamycin derivative, 17-AAG, developed at NCI in collaboration with the pharmaceutical company Kosan Biosciences, have now been completed in the United States and the United Kingdom. None, Dr. Neckers says, was a "home run," but that's typical for phase I trials, which are principally intended to establish safety measures, such as the maximum dose at which clinical and/or biological activity can be detected without causing life-threatening toxicities.
However, in a phase I trial of 17-AAG conducted in the United Kingdom on patients with a variety of solid tumors, two patients with advanced melanoma had sustained periods of stable disease, one of which lasted for nearly 4 years, says the study's leader, Dr. Ian Judson of the Institute of Cancer Research.
More than 20 phase II trials of 17-AAG - alone, or in combination with chemotherapy or targeted agents - are under way. The trials cover a broad range of indications, including advanced breast cancer, prostate cancer, and an assortment of leukemias.
Dr. Jeff Moley from the Siteman Cancer Center of the Washington University School of Medicine is leading a phase II trial of 17-AAG to treat two different kinds of thyroid cancer, including medullary thyroid cancer (MTC). RET, the protein that fuels MTC, is yet another HSP90 client, and Dr. Moley's research has demonstrated that 17-AAG inhibits RET activity.
"There is no standard of care for MTC patients with distant metastases who are no longer taking up radioactive iodine," Dr. Moley says. With 17-AAG, he adds, "We are plowing new ground."
The drug is also being tested in patients with chronic myelogenous leukemia who have developed resistance to perhaps the most famous and effective targeted drug, imatinib (Gleevec).
As it turns out, says Dr. Luke Whitesell, a pediatric oncologist at the University of Arizona currently on leave at the Whitehead Institute for Biomedical Research in Massachusetts, imatinib-resistant leukemia cells "retain their sensitivity for geldanamycin and, if anything, become more sensitive to it."
Dr. Whitesell, who was part of Dr. Neckers' team that discovered geldanamycin's prowess for inhibiting HSP90, is focusing much of his research on HSP90's role in allowing cancer cells to evolve and develop resistance to a given treatment.
"Acquired resistance is a fundamental barrier to curing many cancers," he says. "Within tumors, you've got a genetically unstable and heterogeneous population of cells with tremendous selective pressures placed on them. Evolution to more malignant, drug-resistant phenotypes over time is an inevitable, but poorly understood consequence."
His theory is that HSP90 not only moderates the impact of potentially lethal mutations in cancer cells, but also can preserve those mutations that confer resistance.
"If you could control cancer cells' ability to evolve, it could make other treatments more effective," he argues. In fact, cell line and animal model studies of cervical and lung cancer have shown that 17-AAG can enhance the effectiveness of what would otherwise be suboptimal radiation therapy.
Work is already under way at NCI and several small biotechnology companies to develop next-generation HSP90 inhibitors. 17-DMAG, an agent developed at NCI in collaboration with Kosan, is now in phase I trials. At least six other companies/laboratories are working on their own novel HSP90 inhibitors.
Lani, It is so kind of you to follow up. I haven't read it all but will after forwarding. My friend is a BC buddie, who stepped forward when she heard I was diagnosed. She's a year ahead, same doc. I didn't know she had BC before but she became my email mentor, ie. what to expect from AC, taxol and what to do with your hair.
She was clear as of May. Last week my husband talked to hers and they're talking hospice. She has not communicated so as not to discourage(sp) me. I might be bummed, but I'd rather talk. She is a pharmacist so she should have a better grip on this than most. I've emailed, no reply. I'm worried.
Thanks again as I know you do this to help and this can be so taxing. Really, since BC I step in for all my freind's illnesses.Make appts, yell at them. It's a tough job, someone has to do it. Best, BB
Lani, PS, my understanding is mets everywhere. Liver, lung and brain. Although she never spelled it out I assume she was a stage 2 or 3 at the start. Our doc has a policy of not scanning if one is aysmtomatic, Hmm.
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