Kapil  Mehta  –  Timeline  of  Events    In  Aug  2011  –  I  submitted  the  package  along  with  letters  of  support  from  my  Department  and  Division  Chairs  to  the  institutional  Promotion  and  Tenure  Committee  (PTC)  for  their  evaluation  to  renew  my  tenure  from  Sept  1,  2013  (I  have  been  working  for  MD  Anderson  since  1983).    In  Nov  2012  -­‐  I  was  informed  that  the  PTC  had  unanimously  approved  my  tenure  renewal  from  Sept  1,  2013  (see  Doc  A)    In  May  2012  –  Dr.  Bogler  (Executive  VP  for  Academic  Affairs)  called  my  office  to  announce  that  Dr.  Ron  DePinho  (President)  overruled  PTC  recommendations    In  June  2012  –  I  met  Dr.  Boggler  to  discuss,  and  he  suggested  that  I  resubmit  my  package  to  the  PTC  with  letters  of  recommendation  from  outside  colleagues  (it  did  not  make  any  sense  as  nothing  significant  would  have  changed  in  5  months    since  the  package  was  evaluated  in  Nov  2012  meeting)    In  late  July  2012  -­‐  I  met  Dr.  Ray  DuBois  (Provost  and  Exec  VP)  who  was  supportive  and  suggested  that  I  ask  for  Faculty  Appeal  Process  (FAP)  to  re-­‐evaluate  the  case  (Doc  B).    In  the  meantime,  Dr.  DuBois  left  MD  Anderson  at  the  end  of  Aug  2013  and  Dr.  Buchholz  was  appointed  interim  to  this  position  by  Dr.  DePinho.    In  Sept  2012  -­‐  I  received  a  letter  from  Buchholz's  office  stating  that  he  has  reviewed  PTC  and  FAP  recommendations  and  has  decided  to  with  hold  decision  not  to  renew  tenure.    Oct-­‐Nov  2012  -­‐  I  requested  the  EVP  to  share  FAP  recommendations  so  that  I  can  prepare  to  meet  Dr.  DePinho  to  discuss.  His  office  wrote  back  that  he  cannot  share  FAP  recommendations  with  faculty  (Doc  C).      I  met  with  the  Faculty  Senate  Chair  to  discuss  my  plight  and  was  introduced  to  Dr.  Louise  Strong,  a  senior  faculty  and  ex-­‐Chair  of  the  Faculty  Senate.  Dr.  Strong  wrote  a  strong  letter  to  Dr.  Buchholz  requesting  him  to  release  FAP  recommendations  in  accordance  with  institutional  policy  (Doc  D)  and  the  EVP  office  in  response  immediately  forwarded  this  document,  which  was  a  big  surprise  to  me.  FAP  strongly  felt  that  President's  decision  was  unjustified  and  agreed  with  PTC's  recommendation  to  renew  my  tenure  (Doc  E).    In  Nov  2012  –  Requested  meeting  with  Dr.  DePinho  to  review  PTC  and  FAP's  recommendations  and  to  know  the  reasons  for  his  adverse  decision.    In  Dec  2012  –  Met  with  Dr.  DePinho  along  with  a  senior  faculty  member  to  discuss  my  accomplishments  and  plans  –  but  he  with  held  the  decision  not  to  renew  tenure  

without  giving  any  reasons  -­‐  the  reaction  of  2  senior  academicians  (from  outside  (Dr.  Davies)  and  inside  the  institute  (Dr.  Legerski)  is  in  Doc  F  and  G  June  2013  –  My  Chair,  Division  Chair  and  Division  Vice  Chair  for  Research  wrote  a  strong  letter  appealing  to  grant  at  least  2-­‐years  extension  to  strengthen  areas  which  the  President  felt  were  weak  and  to  continue  working  on  my  project  that  is  promising  and  likely  to  make  strong  impact  on  cancer  patients  (Doc  H).  But  this  request  was  also  decline  (Doc  I).    I  have  several  other  supporting  documents  affirming  that  the  project  I  am  working  is  highly  promising  and  can  likely  suggest  strategies  to  reverse  drug  resistance  in  cancer  patients,  which  accounts  for  more  than  90%  of  cancer  related  deaths.  I  am  attaching  few  documents  (Docs  J  and  K)  as  examples  to  this.    

Document A

September 3, 2012

TO: Dr. Raymond DuBois

Provost and Executive Vice President

Unit 1492

From: Kapil Mehta, Ph.D.

Department of Experimental Therapeutics

Unit 1950

SUB – Term-tenure Renewal Appeal

Dear Dr. DuBois:

As a follow up of our recent meeting on Aug 27, 2012 and my letter of July 9, 2012, I am submitting addition-al information to support my request for re-evaluation of Dr. DePinho’s decision to terminate my tenure. Ac-cording to the Institutional Policy (#ACA0041), I wish to file a formal appeal to this negative decision in view of the facts that:

a) The “Promotion and Tenure Committee (PTC)” unanimously has approved my tenure renewal; and

b) My accomplishments and achievements during current tenure (since 2006), summarized below, clearly meet or exceed the criteria and expectations for ‘Term Tenure Renewal” described in the ‘Institutional Operating Manual’.

Background: I joined M.D. Anderson cancer center in 1983 as a postdoctoral fellow, was promoted to ten-ure-track Assistant Professor position in 1985 and through the ranks to full professor in 1999. During these 29 years, I have worked hard and shed sweat and tears to fulfill my dream of making some difference in cancer patients’ life. I am proud to mention here that some of our lab-based research has lead to clinical benefits and monitory returns to the institution. For example, launching of ‘Abelcet’ for treatment of fungal infections in cancer patients resulted from years of work in our laboratory. In addition, Atragen® developed by our group has shown great promise in inducing long-term CRs (>10 yrs) in APL patients. More recently, the development of liposomal-curcumin is currently undergoing clinical trial for treatment of pancreatic cancer patients and await-ing another clinical trial in Head and Neck cancer Patients.

My most recent project and long-term passion to understand the biology of a pro-inflammatory protein TG2

Document B

in cancer cells has yielded some very interesting and compelling evidence supporting its role as an effective target for reversing the chemo-resistance and preventing metastatic progression of cancer. Multiple tumor types (breast, prostate, ovarian, pancreatic, melanoma, etc.) express elevated levels of TG2 and its expression cor-relates with poor disease outcome. Our group was the first to show that TG2 expression promotes drug resis-tance and metastatic phenotype by inducing mesenchymal transition (EMT) and stem cell traits in epithelial cancer cells. Down regulation of TG2 attenuates tumor growth, metastases, and sensitizes orthotopically grow-ing tumors to chemotherapy. Based on this knowledge, we have identified inhibitors to block TG2-regulated pathways. Two patent applications have been filed by the University of Texas System to protect this invention. We are collaborating with several investigators to develop and test several therapeutic modalities directed against TG2 to reverse chemoresistance and block metastasis of early pre-neoplastic lesions.

Publications: (Appendix A) - Since 2006, my lab has published 32 research articles (21 peer reviewed and 11 invited reviews) in journals such as, Cancer Research, Clinical Cancer research, Oncogene, Breast Cancer Research, Biochemical Pharmacology, and PLoS One. In addition, several manuscripts and invited reviews are currently under review (J Clin Invest, PNAS, Brest Cancer Res) or are in preparation.

Patents: (Appendix B) Targeting of a novel inflammatory pathway has led to 2 patent applications. In addition, 2 US patents for the discovery of a novel intravenous formulation (liposomal-curcumin) and antibody-based immunotoxin were approved by the US Patent and Trade Office.

Funding: (Appendix C) My research efforts during current tenure period were supported by an RO1, R21, and a project grant under melanoma SPORE from the NCI, Investigator initiated award from Susan Komen Founda-tion, and Perot Foundation. In 2009, I was also awarded the AACR-PanCan grant; two of these grants ran out in Feb/April 2012.

I am aware of the current transient hiatus in my funding status, but in prevailing funding environment it is fairly common that investigators go through such funding crisis. I submitted several applications to various funding agencies and two RO1s have received close to fundable score. I am confident that my revised grant applications will soon be funded.

Impact of my recent research: (Appendix D)

· Office of Technology at MD Anderson is negotiating licensing agreements with two different companies for our TG2-related technologies.

· Chaired (July 15-20 2012) and co-chaired (July 2010) the prestigious Gordon Research Conference on Trans-glutaminases in Human Disease Processes.

· Our work received ‘Special Interest citation for Drug Development’ in 2012 Global Medical Discovery.

· Our published work was included in NCI-Sophic Cancer Biomarkers knowledgebase data and was covered in News Release on March 20, 2007; July 15, 2008; and on October 19, 2010.

· Edited a monograph on ‘Drug resistance in Cancer’ in 2009 that received more than 3600 download requests in past 3 years.

· Invitations to organize and/or to present our data at various International Conferences.

As evident from these accomplishments, it was no surprise that the PTC had unanimously approved (9 for, 0 against) the renewal of my term-tenure. However, despite all these positive attributes, my tenure renewal was declined by the President, Dr. DePinho. I have full confidence in the sincere, honest, and rational system oper-ating at the MD Anderson. I, therefore, strongly refute the negative decision and urge you to reconsider my re-quest and PTC’s approval of my tenure renewal so that I can continue to focus on our mission of curing cancer through research and education.

Yours sincerely,

Kapil Mehta, Ph.D.

*Encls.

Outline of credentials

Appendix A, B, C, and D

News Releases

*In addition, I have requested:

Peter Davies, MD, Ph.D. - Professor and Director, Center for Translational Cancer Research,

Texas A&M Health Sciences Center, Houston, TX 77030, and

Richard L. Eckert, Ph.D. - Professor and Chair John F.B. Weaver Distinguished Professor Biochemistry and Molecular Biology, University of Maryland, Baltimore, Maryland

to send letters of support directly to Dr. Ray DuBois. However, additional letters can be requested from other experts working in the field transglutminases.

Document C

Document D

From: Strong, Louise C5ent: Thursday, October 25, 2012 02:52 PMTo: Buchholz, Thomas ACc: Mehta,KapilSubject: non-renewal of tenure

Tom,

As Past Chair of the Senate Oversight Committee on Conflict Resolution I am assisting Or. Kapil Mehta in hJs preparation for appeal to Or. OePinho of tlis non-renewal of tenure. While his major issue is his passion for the science and its potential at this time, there are some other issues.

He reviewed with me the events following his initial notice of unanimous approval of tenure renewal by the PTC, followed by the letter some months later of non-renewal of tenure, his appeal to Dr. DuBois who met with him and presumably recommended he request a Faculty Appeals Panel (FAP), and your review of the FAP report.

Having spent several years reviewing and suggesting revisions for the Conflict Resolution Policy which includes the Faculty Appeals Panel, I have several concerns and a request. I don’t know exactty how this appeals process got started, but a FAP was not the appropriate process for tenure non-renewal.

In fact, FAP is specifically excluded from use of appeals for non-renewal of tenure (ACA0041). Thus the finding that there was not an arbitrary or capricious decision is not relevant. What may be more important was that the Panel (per your letter) did not find a reasonable basis for the action of non-renewal of tenure.

I understand that Dr. Mehta has requested a copy of the FAP findings as this might be helpful in his preparation to meet with Dr. DePinho. There are ample precedents for release of the FAP findings to the appealing party, the policy does not preclude that action.

Dr. Mehta and I would be glad to discuss these concerns with you prior to his meeting with Dr. DePinho scheduled for Tuesday, October 30, at 10 am. Thanks very much for helping him to make his case.

Sincerely,Louise

Louise C. Strong. MDSue and Radcliffe Killam ChairProfessor, Dept of GeneticsMD Anderson Cancer Center1515 Holcombe Blvd, Unit 209Houston, TX 77030lstrong@mdanderson.org713 792-2589

Document E

Davies, Peter <pdavies@ibt.tamhsc.edu>To: Kapil MehtaRe: Follow-upJanuary 24, 2013 10:48AM

Kapil

That is a very strong letter of support in response to your appeal. I am deeply surprised that the administration of the University would choose to override unanimous recommendations from the PTC and FAP committees and this level of support from the Appeals Committee.

Is there any possibility of the institution at least accepting their recommendation for a “grace” period to allow you t ime to re-direct your career??

I will certainly keep my eyes open for any interesting opportunities - nothing on the radar screen at present.

So sorryPete

From: <Mehta>, Kapil <kmehta@mdanderson.org>Date: Thursday, January 24, 2013 9:45AMl o: Davies Peter <pdavies@ibt.tamhsc.edu>Subject: Re: Follow-up

Hi Pete hope you are doing good and heading well into the new year!!

I wanted to share with you the Faculty Appeal Panels’ recommendation which look positive. Despite unanimous approval by the PTC and FAP recommendation, it is obvious that some agenda rather that qualifications arebehind the decision not to renew tenure.

I should be starting to look for a position outside the MDACC. Please let me know if come across any suitable position.

My major goal is to continue working with TG2 and developing inhibitors that will induce openconformation and block TG2/NF-kB loop. Please see recent paper attached.

Regards!Kapil713-792-2649

Document F

Legerski,Randy J <rlegersk@mdanderson.org>To: Kapil Mehta , Cc: Killary,Ann M <akillary@mdanderson.org>Re: Faculty Letter Response from Dr. DePinhoJanuary 2, 2013 7:47 PM

Dear KapilI’m very sorry to hear about this decision. I believe it to be incredibly unfair and in no way justified. I’ll discuss this with the senate leadership to determine what options are available.

RandySent from my iPhone

On Jan 2, 2013, at 7:38 PM, “Mehta,Kapil” <kmehta@mdanderson.org> wrote:

Dear Randy and Ann:Happy new year.I am forwarding Dr. DePinho’s memo regarding my tenure renewal. Once again his decision has surprised me. I am still not clear the reasons for his negative decision. I am sure you will agree that the meeting went very well and everything looked positive. Is there anyway Faculty Senate can help me know why I am being treated like this after 29 years of my dedicated service. Please let me know the next step - this definitely is not the way I want to end my career. I am sorry to keep you bugging, but it is an important issue for the faculty. I am down with flue but hopefully will be back to work by tomorrow. I w ill call you tomorrow or on Friday. Thanks.

KapilKapil Mehta, Ph.D.Professor of Cancer Medicine (Biochemistry),Department of Experimental Therapeutics - Unit 362UT M.D. Anderson Cancer Center1515 Holcombe Blvd.Houston, TX 77030Ph (713)792-2649: FAX (713)745-4167

From: Cole,AnnaSent: Wednesday, January 02, 2013, 4:39 PMTo: Mehta,KapilSubject: Faculty Letter Response from Dr. DePinho

Correspondence sent on behalf of Dr. DePinho

Dear Dr. Mehta,Attached please find Dr. DePinho’s response to your faculty appeal. The hard copy of this correspondence will be delivered to your office via courier.If you have any questions please do not hesitate to contact our office.Anna K. Cole

Office of the PresidentSr. Executive AssistantUT MD Anderson Cancer Center713/563-4503<Dr. Mehta. pdf>

Document G

Document H

Document I

M.D. Anderson Identifies TG2 As a Potential Target in Chemo-Resis-tant Ovarian CancerPosted by Paul Cacciatore on July 15, 2008

“Scientists from The University of Texas M. D. Anderson Cancer Center have found overexpression of tissue type transglutami-nase (TG2) in ovarian cancer is associated with increased tumor cell growth and adhesion, resistance to chemotherapy and lower

overall survival rates. When researchers targeted and silenced TG2 in animal models, cancer progression was reversed, suggesting the protein may also provide a novel therapeutic approach for late-stage ovarian cancer.”

“Scientists from The University of Texas M. D. Anderson Cancer Center have found overexpression of tissue type transglutaminase (TG2) in ovarian cancer is associated with increased tumor cell growth and adhesion, resistance to chemotherapy and lower overall survival rates. When researchers targeted and silenced TG2 in animal models, cancer progression was reversed, suggesting the protein may also provide a novel therapeutic approach for late-stage ovarian cancer.

These findings in the July 15th issue of Cancer Research by a team of researchers led by Anil K. Sood, M.D., professor in the Depart-ments of Gynecologic Oncology and Cancer Biology, and Kapil Mehta, Ph.D., professor in the Department of Experimental Therapeu-tics at M. D. Anderson, are among the first to explore TG2′s functionality in ovarian cancer.

‘TG2 appears to fuel different types of cancer through multiple molecular pathways, making it an important therapeutic target,’ said Mehta, whose lab also has connected TG2 overexpression to drug-resistant and metastatic melanoma, breast cancer and pancreatic cancer.

‘Drug resistance and metastasis are major impediments to the successful treatment of ovarian cancer and until now we had little infor-mation about the role TG2 played in ovarian cancer,’ Sood said. ‘We began to see its story unfold as we translated this data from tissue samples to cell lines to animal models.’

The American Cancer Society estimates 15,000 U.S. women will die from ovarian cancer this year. Most patients present with advanced stage disease that has spread beyond the primary tumor site. More than 70 percent of ovarian cancer patients will suffer a recurrence and eventually succumb to the disease.

Higher TG2, lower survival

The study, which examined 93 ovarian cancer samples of ranging stages, found that high levels of TG2 corresponded with signifi-cantly lower patient survival than those with low levels of TG2. Sixty-nine percent of high-stage ovarian cancers overexpressed TG2 compared with 30 percent of low-stage cancers. In-depth analysis demonstrated that tumors which overexpressed the protein tended to have an increased ability to invade healthy tissue and to survive or avoid the affects of chemotherapy.

Document J

‘From this investigation it became clear that TG2 activates the survival pathway p13K/Akt in these tumors, explaining the adverse, re-sistant behavior we observed on a molecular level,’ said Sood. ‘We then focused on whether silencing TG2 would block these effects.’

Researchers shut off TG2 with a small interfering RNA strand (TG2 siRNA) targeted to the protein, reducing the ability of the tumor cells to invade and killing them through programmed cell death, or apoptosis. ‘When exposed to this potent targeted therapy, ovarian cancer cells greatly reduced cancer cell proliferation and blood vessel development, while increasing apoptosis,’ said Sood.

Mouse model studies of chemotherapy-sensitive and chemotherapy-resistant models showed considerable antitumor activity both with TG2 siRNA alone and in combination with docetaxel chemotherapy. The combination therapy of TG2 siRNA with docetaxel reduced tumor weight by 86 percent, proving to have the greatest efficacy compared to control groups or those without chemotherapy.

‘While it remains to be seen if these results will translate in humans, looking ahead long term, it will be an attractive option against advanced ovarian cancer,’ said co-author Gabriel Lopez-Berestein, M.D. professor in the Department of Experimental Therapeutics at M. D. Anderson.

TG2 fuels pancreatic cancer differently

Sood and Lopez-Berestein, have developed siRNA therapy by packaging the gene-silencing strips of RNA in a fatty nanoparticle called a liposome and delivering it intravenously. TG2 is the third protein they have targeted in preclinical research. Sood and Mehta are moving TG2 siRNA toward Phase I clinical trials for ovarian and pancreatic cancers.

TG2 acts through different pathways in other types of cancer, Mehta noted. For example, TG2 overexpression causes the degradation of the tumor-suppressing protein PTEN in pancreatic cancer, Mehta and colleagues reported in Clinical Cancer Research in April. With PTEN out of the picture, pancreatic cancer is protected from a separate type of cell death called autophagy. In a separate paper, they showed that silencing TG2 with the siRNA liposome reduced tumor size, slowed metastasis and enhanced the effect of gemcit-abine chemotherapy.

‘This aberrant protein is doing so many different things, you would have to develop a small-molecule drug to block each function,’ Mehta said. ‘Liposomal siRNA is exciting because it takes out TG2 completely, blocking everything that it does.’

Research was funded by grants from the National Cancer Institute, including M. D. Anderson’s Specialized Program in Research Ex-cellence in Ovarian Cancer grant, a program project development grant from the Ovarian Cancer Research Fund, Inc., and the Zarrow Foundation.

In addition to Sood, Mehta and Lopez-Berestein, authors include Jee Young Hwang, M.D., Lingegowda S. Mangala, Ph.D., co-first authors, and Yvonne G. Lin, M.D., William M. Merritt, M.D., Whitney A. Spannuth, M.D., Alpa M. Nick, M.D., Derek J. Fiterman, M.D., and Robert L. Coleman, M.D., all of M. D. Anderson’s Department of Gynecologic Oncology; Jansina Y. Fok, also a co-first author, and Pablo E. Vivas-Mejia, Ph.D., both of the Department of Experimental Therapeutics; and Michael T. Deavers, M.D., of M. D. Anderson’s Department of Pathology. Hwang is also with the Department of Obstetrics and Gynecology, Dongguk University of College of Medicine, Kyung-ju, Korea. 07/15/08”

Quoted Source: TG2 Identified as Potential Target in Chemo-Resistant Ovarian Cancer – M. D. Anderson team silences protein with siRNA, implicates TG2 in fourth cancer, The University of Texas, M.D. Anderson Cancer Center News Release, July 15, 2008 (summarizing the findings of Clinical and biological significance of tissue transglutaminase in ovarian carcinoma; Sood, AK et. al, Cancer Res. 2008 Jul 15;68(14):5849-58.)

Newsroom

Protein Found to Shield Pancreatic Cancer Cells from Self-DestructionM. D. Anderson News Release 03/20/07 An overexpressed protein protects human pancreatic cancer cells from being forced to devour them-selves, removing one of the body’s natural defenses against out-of-control cell growth, researchers at The University of Texas M. D. Anderson Cancer Center report in the March issue of Molecular Cancer Research.

The protein tissue transglutaminase, known by the abbreviation TG2, previously has been found by researchers

at M. D. Anderson and elsewhere to be overexpressed in a variety of drug-resistant cancer cells and in cancer that has spread from its original organ (metastasized).

“In general, you rarely see overexpression of TG2 in a normal cell,” says Kapil Mehta, Ph.D., professor in the M. D. Anderson Department of Experimental Therapeutics, who began 10 years ago studying TG2 as an inflam-matory protein.

Mehta and colleagues in the past year have connected TG2 overexpression to drug-resistant and metastatic breast cancer, pancreatic cancer and melanoma.

Expression of TG2 is tightly regulated in a healthy cell, Mehta says, and is temporarily increased in response to certain hormones or stress factors. “However, constitutive expression of this protein in a cancer cell helps confer protection from stress-induced cell death,” Mehta says. “We are developing TG2 as a pharmaceutical target and are now working with a mouse model to that end.”

The mechanisms by which TG2 might promote drug-resistance and metastasis have remained elusive, the researchers note. In this paper, the M. D. Anderson team shows in lab experiments that inhibiting the protein in pancreatic cancer cells leads to a form of programmed cell suicide called autophagy, or self-digestion.

TG2 was inhibited in two separate ways. First, the researchers blocked another protein known to activate TG2. Secondly, they also directly targeted TG2 with a tiny molecule known as small interfering RNA tailored to shut down expression of the protein.

In both cases, the result was a drastic reduction of TG2 expression (up to 94%) and telltale signs of autophagy in the cancer cells, which became riddled with cavities called vacuoles.

When autophagy occurs, a double membrane forms around a cell organ, or organelle. This autophagosome then merges with a digestive organelle called a lysosome and everything inside is consumed, leaving the vacuole and a residue of digested material. If enough of this happens, the cell dies.

Gabriel Lopez-Berestein, M.D., professor of experimental therapeutics and study co-author, notes that the re-search also shows that the self-consuming cell death prevented by TG2 is independent of a prominent molecular pathway also known to regulate autophagy called the mammalian target of rapamycin.

“Targeting TG2, or its activating protein PKC, or both, presents a novel and potentially effective approach to

treating patients with pancreatic cancer,” Lopez-Berestein said. Research in the mouse model remains in the early stages, the researchers caution.

The researchers also show that the TG2 pathway also is separate from another, better known, form of pro-grammed cell death called apoptosis.

Apoptosis, like autophagy, is a normal biological defense mechanism that systematically destroys defective cells by forcing them to kill themselves. In apoptosis, the cells die via damage to their nucleus and DNA, with other cellular organelles preserved. Autophagy kills by degrading those other organelles while sparing the nucleus.

Mehta’s lab reported in a Cancer Research paper last September that TG2 overexpression also activates a protein called nuclear factor-kB known to play a role in regulating cell growth, metastasis and apoptosis. This pathway, Mehta explained, could make TG2 an attractive target for other forms of cancer as well.

Co-authors with Mehta and Lopez-Berestein are: co-first authors Ugur Akar, Ph.D., and Bulent Ozpolat, M.D., Ph.D., and Jansina Fok, all of the Department of Experimental Therapeutics, and Yasuko Kondo, M.D., Ph.D, of the M. D. Anderson Department of Neurosurgery.

Funding for this research was provided by the National Cancer Institute of the National Institutes of Health.

NewsUniversity of California - UC Newsroom | Turmeric enhances effect of chemo drug 1

http://www.universityofcalifornia.edu/news/article/24327

Turmeric enhances effect of chemo drug

Date: 2010-10-19

Contact: Kim Irwin

Phone: (310) 206-2805

Email: kirwin@mednet.ucla.edu

Curcumin, the major component in the spice turmeric, when combined with the chemotherapy drug Cisplatin ,

enhances the chemotherapy ‘s suppression of head and neck cancer cell growth, researchers with UCLA’s Jonsson

Cancer Center have found.

A naturally occurring spice widely used in South Asian and Middle Eastern cooking, turmeric has long been known to

have medicinal properties , attributed to its anti-inflammatory effects. Previous research has shown it can suppress the

growth of certain cancers, said the study’s lead author, Dr. Marilene Wang, a UCLA professor of head and neck

surgery and a Jonsson Cancer Center researcher .

“Head and neck cancers, particularly cases diagnosed in a later stage, are terrible cancers that often require very

radical surgeries and chemotherapy and radiation ,” Wang said. “They often don’t present until late, and the structures

in the head and neck are so vital that our treatments often cause disfigurement and severe loss of function. So using

non-toxic curcumin as a treatment was a very appealing idea.”

The study, done in cells in Petri dishes and then in mouse models, appears in the October issue of the journal

Molecular Cancer Therapeutics .

In India, women for years have been using turmeric for medicinal purposes , as an anti-aging agent rubbed into their

skin, to treat cramps during menstruation, as a poultice on the skin to promote wound healing and as an additive in

cosmetics, said scientist Eri Srivatsan, a UCLA adjunct professor of surgery and a Jonsson Cancer Center researcher

who, along with Wang, has been studying curcumin and its anti-cancer properties for six years.

A 2005 study by Wang and Srivatsan first showed that curcumin suppressed the growth of head and neck cancer

cells, initially in cells and then in mouse models. In the animal studies, the curcumin was applied directly onto the

tumors in paste form because it did not dissolve in saline, which would have allowed it to be injected.

In need of a better way to deliver the curcumin, the team collaborated with Dr. Kapil Mehta of the University of Texas ‘

MD Anderson Cancer Center and found that encapsulating the curcumin in a liposome, an artificially prepared

vehicle that enclosed the spice component within its membrane, made the treatment injectable . The curcumin was

injected into the tail vein of a mouse, where it circulated into the blood stream, slowing down and eventually stopping

the cancer growth, a study in 2008 found.

“This was a very positive finding , developing an efficient way to deliver the treatment,” Wang said. “Our study also

showed that the curcumin was very well tolerated.”

In the current study, the team wanted to combine the curcumin with the chemotherapeutic drug Cisplatin , which is

very toxic at the doses needed to fight head and neck cancers, damaging kidneys, the ears and the bone marrow.

They hoped that if they added curcumin to the mix, they might be able to lower the Cisplatin dose and cause less

organ damage. Their finding , that the curcumin made the Cisplatin work better, was very promising , Wang said.

“We knew that both the curcumin and the Cisplatin , when given alone , had an effect against head and neck cancers,”

Wang said. “This finding that curcumin enhances Cisplatin means that in the future we may be able to give this

chemotherapy in lower doses.”

The study noted that “the mechanisms of the two agents through different growth signaling pathways suggest

potential for the clinical use of sub-therapeutic doses of Cisplatin in combination with curcumin, which will allow

effective suppression of tumor growth while minimizing the toxic side effects.”

The study found that curcumin suppressed head and neck cancer growth by regulating cell cycling, Srivatsan said. It

binds to an enzyme and prevents the enzyme IKK, an inhibitor of kappa B kinase, from activating a transcription factor

called nuclear factor kappa B (NFκB), which promotes cancer growth. Cisplatin ‘s suppressive action involves a

different pathway, through the tumor suppressor proteins p16 and p53, both proteins that also inhibit the activity of

cancer growth promoter NFκB.

“We needed to know the mechanism to help us translate this from the lab into the clinic,” Wang said. “That information

will help us make better decisions on how to design therapies .”

The next step in the clinical setting is to give patients oral curcumin prior to surgery and, after surgery, study the

excised tumors to determine curcumin’s effect on tumor markers, specifically whether there is reduced expression of

markers such as the growth-promoting NFκB. Researchers also will be monitoring to determine if the curcumin results

markers such as the growth-promoting NFκB. Researchers also will be monitoring to determine if the curcumin results

in any side effects. After that, the team would give curcumin to patients also getting chemotherapy and radiation to

see if the tumor suppression found in the cells lines and mouse models can be replicated in humans.

Although turmeric is used in cooking, the amount of curcumin needed to produce a clinical response is much larger,

about 500 milligrams. Expecting a positive effect through eating foods spiced with turmeric is not realistic, the

researchers said.

Curcumin also has a suppressive effect on other cancers, Wang said, including breast, colon and pancreatic cancers.

However , the mechanism of suppression in those cancers has not yet been uncovered . It also may be effective

against Alzheimer ‘s disease and aging , Wang said.

The study was funded by the Veterans Affairs Greater Los Angeles Surgical Education Research Center, the UCLA

Academic Senate, the National Institutes of Health and the U.S. Department of Veterans Affairs.

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in

disease research, prevention , detection, control, treatment and education . One of the nation’s largest comprehensive

cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading -

edge clinical studies. In July 2010, the center was named among the top 10 cancer centers nationwide by U.S. News

& World Report, a ranking it has held for 10 of the last 11 years.

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