News from the CPRIT

Email not displaying correctly? View it in your browser. At its February 25, 2013 meeting, the CPRIT Oversight Committee approved proposed changes to existing agency rules and the addition of three new rules.  The changes proposed are designed to implement many of the State Auditor’s recommendations concerning ethics, conflicts of interest, grant review and documentation of the agency’s grant processes. The proposed rule changes and new rules appear in the March 15, 2013 edition of the Texas Register.  Public comment is accepted for 30 days following publication and is due no later than 5:00 pm on April 15, 2013.  At its meeting in late April, the Oversight Committee expects to consider final rules reflecting the comments received. Individuals or organizations interested in providing input on the rule changes and new rules may do so by sending written comments to Ms. Kristen Pauling Doyle, General Counsel, Cancer Prevention and Research Institute of Texas, P. O. Box 12097, Austin, Texas 78711.  Comments may also be submitted electronically to kdoyle@cprit.state.tx.us or by facsimile transmission to 512/475-2563.  Comments must be received no later than 5:00 pm on April 15, 2013. http://www.cprit.state.tx.us Unsubscribe from this list | Forward to a friend| Update your profile Our mailing address is: Cancer Prevention and Research Institute of Texas 211 E 7th Street Ste 300 Austin, Texas 78701 Add us to your address book Copyright (C) 2013 Cancer Prevention and Research Institute of Texas All rights reserved.

Jakafi		Superior reductions in spleen volume and improvements in Total Symptom Score (TSS) vs placebo.1,2 Learn more at www.jakafi.com.
	JAK Pathway	About Jakafi	IncyteCARES	Learn more >
	Jakafi®—the first and only FDA-approved agent for intermediate or high-risk myelofibrosis1,3 Dear Dr Kankonde, Consider Jakafi for your patients with intermediate or high-risk myelofibrosis. Jakafi reduces splenomegaly and improves the symptoms of myelofibrosis, as measured by TSS.* Symptoms measured by TSS were abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. In a clinical study, most patients receiving placebo experienced increased splenomegaly and worsening of symptoms.1,2 Jakafi regulates JAK1 and JAK2 signaling1,2 • Dysregulated Janus kinase (JAK) signaling is a key feature of myelofibrosis4 • Splenomegaly and debilitating symptoms of myelofibrosis have been linked to dysregulated JAK signaling5 • Dysregulated JAK signaling may occur via many mechanisms, including3,6-13 — JAK2 mutations — Receptor mutations (eg, MPL mutations) — Increased JAK1 signaling — Excess cytokines — Damaged intracellular signaling mechanisms (eg, those involving SOCS) View the Jakafi Mechanism of Action (MOA) video > MPL=myeloproliferative leukemia virus oncogene; SOCS=suppressor of cytokine signaling. • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache
	Jakafi demonstrated superior reductions in spleen volume and significant improvements in symptom scores1,14,15 41.9% vs 0.7%1,2† Patients achieving a >35% reduction in spleen volume at 24 weeks vs placebo (COMFORT-I) (P < 0.0001) 28.5% vs 0%1,2‡ Patients achieving a >35% reduction in spleen volume at 48 weeks vs best available therapy (BAT) (COMFORT-II) (P < 0.0001) 45.9% vs 5.3%1,2† Patients achieving a >50% improvement in TSS at 24 weeks vs placebo (COMFORT-I) (P < 0.0001) Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo.2 Each bar represents an individual patient's response. Each bar represents an individual patient's response. Worsening of TSS is truncated at 150%. Please see Important Safety Information. Learn more about how Jakafi can help your patients >   * TSS was captured by the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0), a daily patient diary recorded for 25 weeks. Symptom scores ranged from 0 to 10 with 0 representing symptoms "absent" and 10 representing "worst imaginable" symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the group receiving Jakafi and 16.5 in the placebo group.1,2 † Based on COMFORT-I, a randomized, double-blind, placebo-controlled study in patients with myelofibrosis who were refractory to or not candidates for available therapy.1,14 ‡ Based on COMFORT-II, an open-label, randomized study of Jakafi vs BAT.1,15
	IncyteCARES (Connecting to Access, Reimbursement, Education and Support) IncyteCARES offers free educational support for your patients taking Jakafi. Order the IncyteCARES Patient Starter Packet > Learn about Jakafi View the Jakafi MOA video and learn about how Jakafi works. Order the IncyteCARES Patient Starter Packet Give your patients this resource, which provides information about Jakafi treatment and patient support services. Sign up for more information Stay current with the latest news and information about Jakafi.
	Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 x 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 x 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Please see Full Prescribing Information. References: 1. Jakafi Prescribing Information. Incyte Corporation. November 2011. 2. Data on file. Incyte Corporation. 3. Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:3109-3117. 4. Anand S, Stedham F, Gudgin E, et al. Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. Blood. 2011;118:1610-1621. 5. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117-1127. 6. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790. 7. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673-683. 8. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459-468. 9. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:1140-1151. 10. Kralovics R. Genetic complexity of myeloproliferative neoplasms. Leukemia. 2008;22:1841-1848. 11. Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol. 2011;29:1356-1363. 12. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009:636-642. 13. Fourouclas N, Li J, Gilby DC, et al. Methylation of the suppressor of cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders. Haematologica. 2008;93:1635-1644. 14. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807. 15. Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798.

CTC Survey Results Released

Inbox

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Andrew Kerry	3:08 AM (3 hours ago)
to me

  Dear MUTOMBO,

We recently ran a survey on Circulating Tumour Cells which questioned stakeholders across drug development, academia, cancer hospitals and the technology sector on the  challenges that they are facing in utilising CTCs in their research.  I think you’ll find the results interesting: 74.3% of respondents in the survey highlighted CTCs as either a "very high" or  "high priority" for their organisation When questioned what was the biggest challenges faced in this field the top  challenge was identified as “Current technology is neither sensitive or specific  enough” (33%) with the second biggest challenge being that “There is no agreed  golden standard for technology” (25.5%) A resounding 48.8% thought that to validate CTCs in the clinic there needs to be  “more clinical trials validating CTCs as a diagnostic/prognostic prospective” These are just some of the revealing answers the survey uncovered. You can download the full survey results from the World CTC Berlin Library. In addition to these exciting results I’d also like to take the opportunity to announce the latest speaker for World CTC Berlin: Sarah Thayer, Associate Professor, Surgery, W. Gerald Austen Scholar in Academic Surgery & Director, Pancreatic Biology Laboratory, Mass Gen Hospital Presentation Title: The Capture, Growth and Genetic Analysis of CTC in PDAC: What  Can it Tell Us About this Disease? Detection of CTC in patients with resectable PDAC using a Screencells Device Methods used to achieve in vitro growth and confirmation of tumorigenicity How selective deep sequencing was used to demonstrate the feasibility of  identifying mutations present in the primary tumour and their corresponding CTC Download the meeting brochure to see the full array of CTC experts on the programme. Kind regards Andrew Andrew Kerry Hanson Wade www.worldctc-berlin.com

Today more field research work in Indianapolis where I discover Carmel reportedly the best place to live in America.  'The number 1 best place to live" and I am there. This is not my impression we are talking about, this is from money magazine as of Sept 2012.  Carmel IN was followed at a distance by McKinney,TX (will go there to visit when I am back in Texas. 3rd place Eden Prairie MN, 4. Newton MA, 5th. Redmond WA
6th Irvine CA.
VISIT THESE QUAINT PLACES TO DISCOVER THE CHARM OF AMERICAN CITIES, AND WRITE TO ME ABOUT.   I REALLY AGREE THIS PLACE IS CHARMING!  JUST WISH I HAD MORE TIME AND MONEY TO ENJOY IT FULLY!

Dr. Robert A. Kirken who has been appointed as the new dean of the UTEP College of Science

UTEP - The University of Texas at El Paso

Congratulations to Dr. Robert A. Kirken who has been appointed as the new dean of the UTEP College of Science. Read more about his announcement here: http://utepn.ws/WkKMol

Gefällt mir nicht mehr · · Teilen · 383 · vor 30 Minuten

ADVANCES IN METASTATIC RENAL CANCER

*IL-2  (High dose) Response rate < 10% but with rare cures
* Medication approved
1. Sunitinib which was compred to Interferon to win approval
2. Avastin in combination to Interferon (not alone) was compared to interferon alone to win approval
3.Pazopanib was compared to placebo to win approval
4.Temsirolimus was compared to Interferon to win approval.
someone thought combining Interferon and Tensirolimus will give a higher response rate, well it did not.  But this bring back the notion that until the MTOR is really amplified, rushing into its inhibition may not bring result.  So timing suggested after failure of VEGF is critical.

5. Pazopanib was compared to Sunitinib, non inferiority proven although Pazopanib had PFS of 8.4 against a 9.5 months accomplished Sutent.  The statical referee came in not statistical difference depite the hair color change of Pazopanib recipient! The hematologic toxicitywere worse with Sutent!

6.New kids on the block (Tivozanib and anti-PD1)
-Tivozanib was compared to Nexavar and came up on top in terms of PFS.  OS not measure because of cross-over

ONE HAS VENTURED TO SUGGEST THAT
START WITH SUTENT
THAN AFINITOR
FOLLOWED BY AXITINIB
THAN ANTI-PD1
----------------------------------------

BUT REMEMBER THAT HISTOLOGY MAY FORCE YOU TO SKIP SUNITINIB
AND INTERFERON-BEVACIZUMAB ARE ALSO SOLID OPTIONS, AND SO REMAINS HIGH DOSE IL-2.

7-AXITINIB (AN ANTI-VEGF(s) ) WAS ALSO MATCHED WITH SORAFENIB IN THE HUTSON ET AL STUDY.AND CAME UP ON TOP FOR PFS.  HOWEVER THE OBSERVERS ARE SAYING THAT IN THE LATEST PHASE III STUDY AXITINIB,ALTHOUGH ACTIVE, DID NOT MEET ITS PRIMARY END POINT.

8.EVEROLIMUS AGAINST PLACEBO WON BIG PFS, BUT NO OS!?

AVASTIN and Blood Vessels

1. Avastin normalizes blood vessel and therefore improves drug delivery
2.Combination with anti-EGFR, shortens PFS
3. Changes endothelium
4. Refractoriness soon develops
5.no cures
6.lack of biomarkers to optimally evaluate,monitor efficacy, and therefore dose optimally
7.Increasing Fibroblast growth factor as a way of dealing with lack of VEGF receptors
?dummy receptor to hijack extracellular - transcription factors increase

INHIBITION OF MTOR

from  R T Kurmasheva, et al

"Thus, inhibition of mTOR may have direct effects on cancer cell proliferation and survival, indirect effects via inhibition of HIF-1α, thus reducing tumour-elicited VEGF, direct effects on vascular endothelial cells, or vascular smooth muscle cells (Humar et al, 2002; Majumder et al, 2004). For example, induction of HIF-1α and VEGF by the CML-associated oncogene, BCR-ABL, is mTOR-dependent (Mayerhofer et al, 2002), and in vitro, rapamycin inhibited VEGF production in primary cultures from BCR-ABL transformed, imatinib resistant, CML (Mayerhofer et al, 2005). The role for mTOR in VEGF production is supported by regulation of HIF-1α by mTOR signalling and increased VEGF in cells deficient in the TSC that negatively regulates mTOR via Rheb (Hudson et al, 2002). However, other studies support a role mainly for PI3K and to a lesser extent mTOR being required for insulin-induced HIF-1α expression (Treins et al, 2002). Our studies indicate that rapamycin treatment has little effect on hypoxia-driven VEGF production in most rhabdomyosarcoma or neuroblastoma cell lines (Kurmasheva et al, submitted). Thus, in these cells it is unlikely that rapamycin would block tumour-derived VEGF, although it may directly block the response of vascular endothelial or other stromal cells in tumour tissue. Potentially, in vivo resistance to mTOR inhibition could be elicited by secretion of angiogenic factors that signal to stromal cells via mTOR-independent pathways to increase proliferation or motility of vascular cells."
------------------------------------------------------------------------------

Yesterday we saw that Anti-VEGF drug induced alteration of vascular endothelium that could eventually bring Hypoxia into the cell, today we add evidence that the Hypoxia may induce HIF expression bringing MTOR overexpression into the battle leading to cancer cellular survival.  THIS INDICATES THAT WHILE CONTINUING AVASTIN, INTRODUCING MTOR INHIBITOR AT THIS POINT MAY BRING A NEW STRATEGY TO REVERSE AVASTIN RESISTANCE, MEANING WHEN PLACENTAL GROWTH FACTOR OVER EXPRESSION IS HIGH (A MARKER OF AVASTIN FAILURE) , IT WOULD BE AN APPROPRIATE TIME TO BRING IN THE MTOR WITHOUT STOPPING AVASTIN.  REMEMBER STOPPING AVASTIN HAS DEVASTATING REBOUND OF CANCER.  AVASTIN HERE SERVES AS A PRIME FOR MTOR!

THE CRCBM RECOMMENDS THIS PIECE OF ARTICLE TO ALL READERS!

Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates

1. Sonja Loges*,
2. Thomas Schmidt* and
3. Peter Carmeliet⇓

+ Author Affiliations

1. Vesalius Research Center (VRC), Leuven, Belgium

1. P. Carmeliet, MD, PhD, Vesalius Research Center, VIB, K.U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium Email: peter.carmeliet@med.kuleuven.be
2. -----------------------------------------------------------------------------------------
3.  
4.  
5. Suffice is to say that the concerns mentioned in this review, which is an excellent review, unveils in pretty good details the insufficiency of a monotherapy attacking an essential function of the cells. Not only will the cell have an answer such as dummy receptors, secondary amplification of transcription factors of growth factors, but escape mechanisms that include escape of the area leading to metastasis.  I should confess that recruiting other cells to help fight the attacker (Myeloid and endothelial cells) showed clearly how much angiogenesis is globally needed.  I would think that the reaction by the NF-kB would be sufficient; with its secondary growth  factor production, induction would be the predictable way.  But clearly, the cell wants restoration of the angiogenic function and finally wins, making Avastin effects short lived.  By inducing Hypoxia, stress becomes a secondary impetus and c-JUN enters the dance and fights again with resulting amplification of growth factor and various dislocation of various cyclins at integrin locations including the Angiopoietins.
6. One of the things that needs to be emphasized or not looked at or discussed in your piece are events happening at the MEK.  You know by now that MEK is clearly amplified either by the cancerous process or in reaction to the blockage or consumption at VEGF.  Tracking MEK is important, because if amplified and mutated it may reverse mesengial transformation and render the cell more omnipotent.  It may be at the center of the observation that blocking both EGFR and VEGF reduces the progression free survival. Events at the MEK need to be scrutinized.
7. You also realize that, in the long run,  MTOR will be secondarily stimulated leading to Telomere preservation (stabilization) and cell surviva
8. The quick restoration of the angiogenic function after cessation of the treatment marks the importance of VEGF.

Your discussion has not only brought up in details the predicted failure of mono-target-therapies, but in the case of an important/critical cellular function being impaired by Avastin, and the resulting multitude of cellular responses. I really thank the authors for this important piece!
Clearly, Avastin is never meant to be a monotherapy, that is the answer!  To all action, there is a reaction. And cells expect action, it is built for them!

METASTATIC COLON CANCER

*It is interesting to note that in current clinical practice  3/4 of Oncologist still give Avastin instead of Cetuximab as their first choice in KRAS wild type metastatic colon cancer, and they chose it in combination with FOLFOX.   Why to do the test at onset.  And 12 cycles won rather than "until disease progression" in Metastatic setting.
* If you worry about Mismatch repair, it did not come up!

*Avastin-Xeloda superior to Xeloda alone with
- progression free survival (PFS) 9.1 months Vs 6.1months
- Overall survival (OS) 20.7 months Vs 16.8 months

* In Maintenance setting, Combining Avastin to Erlotinib was superior to Avastin alone  (OPTIMOX3) in terms of progression free survival.

*In the VELOUR study
Aflibercept +FOLFIRI was superior to Folfiri alone in terms of PFS and OS.

*new kid on the block Regorafenib (brings back use of EUCERIN cream for patients palms)

(CONFERENCE CONTINUES) PANCREATIC CANCER UPDATE:

*FOLFIRINOX definitely in control as first choice for first line
but this option is too toxic in the elderly so a modified version is adopted by some
.*new IMPACT STUDY,  GEMZAR-ABRAXANE is being rapidly adopted as an alternative to FOLFIRINOX for this same and very  reason (Toxicity of Folfirinox)
This combination was reportedly tried in selected clinics (including Eastern Europe) in a Phase III trial, was tried against Gemzar alone
and gave Progression free survival of 5.5 months Vs 3.7 months
                                                      Overall survival 8.5 months Vs 6.7 months     (Von Hoff DD et al.)

Abraxane given at 125 mg/m2 and Gemzar at 1000mg/m2 Q3/4 in the combination arm
----------------------------------------------------------------------------------------------
3rd choice of course was GEMZAR-ERLOTINIB follwed by GEMZAR ALONE.
===========================================================

NOTABLY NO TARGET THERAPY DISCUSSED WHICH NEEDS TO BE CORRECTED FAST!

METASTATIC MELANOMA

1.IPILIMUMAB ( ANTI-CTLA-4), BETTER THAN DTIC
Dose in front line is 10mg/kg every 12 weeks but the FDA approved at 3mg/kg every 3 weeks 4 times
*Ipilimumab is one of the most significant developments here since its curb leads to a plateau state of survival which begins to show at approximately 2 years,
at 1 year, survival in metastatic disease is at 44-46%
at 2 years, it is at 22% (with 3Y survival at 20.8% in STUDY 024)
there after it does not drop off as much, suggesting there are few cures
*This is reminding us the curb of IL-2 in which few cures are observed.
*Ipilimumab is not for those with rapidly progressive disease, activity is delayed.
*Active even in Brain Mets

*10mg/kg did better than 3mg/kg but at greater Toxicity.
-------------------------------------------------------------------------------------------------
2. * IL-2 the "old dog" is still going strong, tough on patients and only given in specialized centers,
still kicking as an option because of the cures it gives
 * Given only to selected patients with skin and lung disease, stress test needed if over 50, and smokers,
after abdominal surgery, wait for 8 weeks before initiating treatment.
*Median duration of response 6.5 months
*17% Response Rate (6% CR) and (11% PR)
69% of those with CR will be cured, and 47% of PR will stay stable (a cure of sort)
-------------------------------------------------------------------------------------
3.VEMURAFENIB for those expressing BRAF-V600  (ON all the times)
90% suppression of pERK needed for clinical activity
* after Vemurafemib, patients respond poorly to Ipilimumab
* gives the longest Progression free survival 15.9 months
*No survival tail here, the lesions quickly melt, but when they come back, death subsequently ensues.
*in one series,patients 20-30 Years of age are 100% BRAF positive
*Combination Ipilimumab and Vemurafenib proved to be too toxic for the Host/patient
*Vemurafenib combination with Anti-MEK could eventually replace the single agent.
---------------------------------------------------------------------------------------------
4. ABRAXANE has replaced DTIC as Chemotherapy to go to first,
other Option Taxol-Carbo in desperate states such as recurrence after failure of Vemurafenib
----------------------------------------------------------------------------------------------
5. New kid on the block, PD-L1, provides a new option for recurrence after Vemurafenib or BRAF
WT mutated patients, "ANTI-DEATH"

Synta announces results from Ganetespib Phase 2b trial on NSCLC

Published on September 29, 2012 at 5:14 AM 

Synta Pharmaceuticals Corp. (NASDAQ: SNTA) today announced results from an interim analysis of the Phase 2b portion of the GALAXY trial, a global, randomized, multi-center Phase 2b/3 study designed to evaluate the efficacy and safety of the Company's lead Hsp90 inhibitor, ganetespib, as second-line treatment for advanced non-small cell lung cancer (NSCLC). The results showed good tolerability for the combination of ganetespib (G) and docetaxel (D), as well as meaningful improvements in overall survival (OS) in adenocarcinoma patients receiving docetaxel plus ganetespib compared to those receiving docetaxel alone. The results were presented by Suresh Ramalingam, MD, Professor, Hematology & Medical Oncology, and Director, Translational Thoracic Malignancies Program, of the Winship Cancer Institute of Emory University, in a poster session at the European Society for Medical Oncology 2012 Congress in Vienna, Austria. A copy of the poster is available at http://www.syntapharma.com/documents/Ganetespib_GALAXY_ESMO_2012_Poster.pdf.
The GALAXY trial is based on a two-stage, operationally adaptive design. The first-stage, randomized, open-label, 240-patient Phase 2b portion of the trial is enrolling Stage IIIB/IV NSCLC patients who have progressed following one prior line of therapy, and is designed to identify the patient population, defined by biomarker or other disease characteristic, for advancement into the Phase 3 portion of the trial.
An interim analysis was planned for when approximately 80% of the target 240 adenocarcinoma patients had been enrolled. A total of 187 patients were enrolled at the time of analysis, of which 172 patients had been entered into the clinical database at the time of data cutoff.
"The preliminary results from GALAXY indicate that the addition of ganetespib to docetaxel is well tolerated and may improve outcomes in patients compared to docetaxel alone," said Dr. Ramalingam, a Principal Investigator of the study. "This includes promising improvements in survival seen across the broad adenocarcinoma population as well as in key predefined patient populations. A well-tolerated combination regimen that extends survival associated with salvage therapy in NSCLC will meet a much awaited need to improve the current standard of care."
Targeting the dependence of cancer cell growth and proliferation pathways on the Hsp90 chaperone represents a new way to interrupt cancer cell signaling and reduce tumor aggressiveness. Hsp90 inhibition by ganetespib simultaneously inhibits multiple critical cancer-promoting pathways, including pathways responsible for tumor metastasis, angiogenesis, and resistance to conventional therapies.

Continued on Next page >>

Posted in: Drug Trial News | Medical Condition News

Tags: Angiogenesis, Biomarker, Breast Cancer, Cancer, Cell, Chemotherapy, Docetaxel, Hematology, Hemoptysis, Immunosuppression, Immunotherapy, Leukemia, Lung Cancer, Medi-Cal, Melanoma, Metastasis, Multiple Myeloma, Myeloid Leukemia, Myeloma, Non-Small Cell Lung Cancer, Oncology, Protein, Radiotherapy, Small Cell Lung Cancer, Smoking, Stem Cell, Translational, VEGF

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TODAY'S CONFERENCE NEWS!

One thing is for sure: current clinical practice of Oncology is miles away from the cutting edge science advancing before it and there is a reason to this fact, only what is clearly established and approved by national institutions reaches the practicing Oncologist.  And clearly, it is important that speakers during Oncology conferences reinvent themselves deep enough to understand the flow of information coming through.  It is easy to tell who knows fully and who is trying to keep up among speakers.   Navigating the world of research while keeping up with clinical studies is the challenge our speakers face.

1.  In lung cancer
-------------------
*In Adenocarcinoma:  Pemetrex +Cisplatin based treatment is still King prior to gene Mutation determination, in Metastatic setting and first line
*But when EGFR and positive is known, Erlotinib came on top! And when progression occurs,
continuing ERLOTINIB, but adding a chemotherapy doublet won!
*Despite great achievements by Target therapy in lung cancer, most of the time it is hard to prove survival benefits because most studies allow cross-over of those failing the chemotherapy-alone arm.
*Afatinib was superior to Cisplatin-Pemetrex in those with Del 19/L858R (EGFR mutation positive)
with Progression free survival 13.6 months Vs 6.9 months in metastatic setting.
*Increasingly, re-biopsy at recurrence is occurring to reassess the status of common Mutations.
It has noted that tumors which were EGFR positive, once they become resistant, they adopt small cell features and respond to Small cell regimens.
* When using a EGFR, continue the drug beyond resistance because in a limited MSKCC series, up to 25% of cancers experience a "FLARE" when TKI (Tyrosine Kinase Inhibitors) were discontinued.  So, while considering options for 2nd line therapy, do not stop TKI.

*Currently tested Mutations:
EGFR, EML4-ALK fusion, MET amplification by FISH (not so much by IHC), ROS-1, PIK3CA (sometime FGFR1)
*"PROXIMITY" TO ROS1 WITH INSULIN RECEPTOR discussed
*IF EGFR positive, rarely you will find KRAS (exclusivity rule discussed)
*in lung cancer :
you find ROS1 in 1.5% of cases,
             ALK + in 5% of cases
             RET + in 2% of cases
             EGFR + in 18% of cases
             HER-2 in 2 % of cases
*Acinar Morphology a cue for ALK positive? and CRIZOTINIB is the answer!

*Now comes OR HAS ARRIVED THE PRACTICE OF "MULTIPLEX TESTING" FOR IDENTIFICATION OF SPECIFIC MUTATIONS.
*Of note: the study showing Taxotere equivalent to Gefitinib in lung cancer cases unscreened for EGFR mutation at onset of trial are challenging the notion of Early EGFR identification!

NEW GANETESPID (+TAXOTERE), THIS IS AN INHIBITOR OF HSP90, A CHAPERONE MOLECULE AND PD-L1   BMS936558

WITH THIS FRAME OF INFORMATION - GO TO WORK!

NEXT: METASTATIC MELANOMA

RECURRENT LIPOSARCOMA

The other day we were in a conference discussing a case of Liposarcoma.  The man was in his 50ies and had been referred to the University surgeon for an extensive abdominal Liposarcoma that needed further resection. The disease had been resected at least twice by the community surgeon before, it had returned with significant peritoneal and pelvic infiltration.  Interval between resections had been in years, but now it was in months.  Clearly, the disease has packed further gene abnormalities now that it is evidently metastatic.  Let me take this back, because despite the widespread invasion in the abdomen, there was no tissue invasion.  There were no clear liver, lung or brain invasion.  This disease was killing a man before our eyes because of clear infiltration of abdominal tissues.
Because of the interval between surgeries, the Oncologist argued that this is a low grade tumor and may not be handled with standard chemotherapy and I strongly believe he was right.  My case with Angiosarcoma did not budge with Gemzar, Taxol followed by MAID,  I am trying AVASTIN ALONE now!
But returning to the case, the hospital and the surgery department are now breathing on the neck of the surgeon because they do not see the point of putting the patient through very expensive surgeries followed by  costly ICU stays every few months. I guess there are potential liabilities linked to the exercise. Particularly because the surgeries were done when this patient was with evident big progression of disease, but asymptomatic still.   Oncologist and Surgeon alike argued we should not wait for symptoms, because it could be inoperable by then, and an aggressive surgery plan is helpful in these local diseases.
With standard chemotherapy out the only thing left is Target therapy as an effective option.  We did not get help from the pathology department since no genetic abnormality testing is done (this is not Mayo or Harvard.  DR KRIS who speaks of gene panels in lung cancer does not live here).  And Votrient, the only  FDA approved drug is indicated in those who failed chemotherapy.  Basically, you have to put this man on chemotherapy that you know will harm him unnecessarily in order to get to Votrient (Pazopanib), an anti-VEGFR(s), Anti-c-KIT, anti-PDGFR a/Beta.  with 3-4 months advantage over placebo.
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FDA NEWS RELEASE

For Immediate Release: April 26, 2012
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA approves Votrient for advanced soft tissue sarcoma
The U.S. Food and Drug Administration today approved Votrient (pazopanib) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. Soft tissue sarcoma is a cancer that begins in the muscle, fat, fibrous tissue, and other tissues.
Votrient is a pill that works by interfering with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.
A rare cancer with many subtypes, soft tissue sarcoma occurs in about 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to approval of Votrient. The drug is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors.
“Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas.”
The safety and effectiveness of Votrient was evaluated in a single clinical study in 369 patients with advanced soft tissue sarcoma who had received prior chemotherapy. Patients were randomly selected to receive Votrient or a placebo. The study was designed to measure the length of time a patient lived without the cancer progressing (progression-free survival). The disease did not progress for a median of 4.6 months for patients receiving Votrient, compared with 1.6 months for those receiving the placebo.
The most common side effects in Votrient-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.
Votrient carries a boxed warning alerting patients and health care professionals to the potential risk of liver damage (hepatotoxicity), which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.
Votrient was granted an orphan drug status designation for this indication. An orphan designation is given to a drug intended to treat a disease affecting fewer than 200,000 patients in the United States. Votrient was first approved in October 2009 for the treatment of advanced kidney cancer.

Votrient is marketed by GlaxoSmithKline of Research Triangle Park, N.C.
For more information:
FDA: Office of Hematology and Oncology Products
FDA: Approved Drugs: Questions and Answers
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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For the sake of argument

1. In this man we know it is a Liposarcoma

therefore the primary deficiency is in the handling of lipid.  Insulin Receptor, may be?  IGFR, IGFBP, PPR1. CCR11
(GOT TO RUN TO CONFERENCE WITH XCENDA IN CHICAGO---TO BE CONTINUED!)

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INTERESTING DEBATES

1.NF1 Mutation is upstream from
BRAF
and MTOR
But NF-1 is Mutated in Melanoma
can infusion of protein resulting from NF-1 be used to strengthen effect of MTOR inhibitor and BRAF inhibitor by maintaining these pathways open!

2.  Discriminating Redundancy in cellular language
same gene base corresponding to same Amino Acid
same receptors at membrane being sensitive by different stimuli
but when it comes to the RAS, nature and intensity need to matter and this also a function of tissue involved!
some time however the nature of the stimulus is more important particularly inside the cell where ie HP90 seems to stimulate more the CoN to achieve PTEN suppression. And you know that CoM stimulation raise Bcl2 level...we will say more in our upcoming article of langaue of the cell as it pertains to pathways!

3. PTEN is repressed by low expression of gene or mislocalization (reported PNUTS 'role) at Nuclear level or both?

CHANGES ARE COMING TO YOU, LIKE IT OR NOT!

SOME PEOPLE REALLY BELIEVE THEY ARE THEY TOO BIG FOR CRITICISM, THEY FEEL OFFENDED WHEN YOU CONFRONT THEM WITH A TRUTH THEY CAN'T BELIEVE.
Everyday Big professors are reminded how important they are by our praises and regular consultations.  Professors grow on us because they have knowledge we believe to be the truth, and because often they are right rather than wrong.  But every time they are solicited, they practice a certain logic they have perfected to come to a logical conclusion.  They pass on this logical process to their students and friends and, as a result, a university culture is created and passed on!  Such a system, however, needs to be challenged once in a while to be made better.  It is made better when it accepts change, because accepting new plausible changes prepares us to wider sorts of challenges, it is the strength of diversity, it prepares us against challenges to come, challenges we will have to reckon with at one point or another. It is the strength of these United States. It is why this country is better prepared than other countries which is somewhat monolithic, culture wise!

When monolithic systems are confronted, when our professors are confronted and when they refuse to face the truthful difference, they reject it with anger and become defensive and somewhat violent (not necessarily physical violence) in their tone.
I was in a recent meeting where I suggested to an eminent oncologist that we look into potential new targeting therapy for a rare type of sarcoma.  An eminent man who I admire became irate or vexed at an unexpected level which surprised me.  It is the truth that everyone nowadays should be looking to target therapy for answers in cancer.  But his reaction was off the wall!   I can understand that evidence based medicine forces us to argue only what has been proven,  but in a university setting, the non-proven should challenge us to look for more, it should be where we start if the goal is to push the envelope further.  I don't know what was in the man's drink to be so offended by the truth we all face, the puzzle that is cancer. I don't know under what "University environment" political pressure he finds himself, so I give him a break, give him slack !  He was just defending his turf !

But one thing for sure, let's be more receptive to change, because it will come, and impose on us whether we like it or not!  You can resist it for a while, but one of these days even your own son or a dear friend will wake you up to it!