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
Document B
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 additional information to support my request for re-evaluation of Dr. DePinho’s decision to terminate my tenure. According 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 tenure-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 awaiting 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
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 correlates with poor disease outcome. Our group was the first to show that TG2 expression promotes drug resistance 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 growing 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 Foundation, 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.
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Chaired (July 15-20 2012) and co-chaired (July 2010) the prestigious Gordon Research Conference on Transglutaminases in Human Disease Processes.
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Our work received ‘Special Interest citation for Drug Development’ in 2012 Global Medical Discovery.
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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.
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Edited a monograph on ‘Drug resistance in Cancer’ in 2009 that received more than 3600 download requests in past 3 years.
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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 operating at the MD Anderson. I, therefore, strongly refute the negative decision and urge you to reconsider my request 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.
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Document D From: Strong, Louise C 5ent: Thursday, October 25, 2012 02:52 PM To: Buchholz, Thomas A Cc: Mehta,Kapil Subject: 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. MD Sue and Radcliffe Killam Chair Professor, Dept of Genetics MD Anderson Cancer Center 1515 Holcombe Blvd, Unit 209 Houston, TX 77030 lstrong@mdanderson.org 713 792-2589
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Document F Davies, Peter <pdavies@ibt.tamhsc.edu> To: Kapil Mehta Re: Follow-up January 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 sorry Pete From: <Mehta>, Kapil <kmehta@mdanderson.org> Date: Thursday, January 24, 2013 9:45AM l 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 are behind 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 open conformation and block TG2/NF-kB loop. Please see recent paper attached. Regards! Kapil 713-792-2649
Document G Legerski,Randy J <rlegersk@mdanderson.org> To: Kapil Mehta , Cc: Killary,Ann M <akillary@mdanderson.org> Re: Faculty Letter Response from Dr. DePinho January 2, 2013 7:47 PM Dear Kapil I’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. Randy Sent 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. Kapil Kapil Mehta, Ph.D. Professor of Cancer Medicine (Biochemistry), Department of Experimental Therapeutics - Unit 362 UT M.D. Anderson Cancer Center 1515 Holcombe Blvd. Houston, TX 77030 Ph (713)792-2649: FAX (713)745-4167 From: Cole,Anna Sent: Wednesday, January 02, 2013, 4:39 PM To: Mehta,Kapil Subject: 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 President Sr. Executive Assistant UT MD Anderson Cancer Center 713/563-4503 <Dr. Mehta. pdf>
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M.D. Anderson Identifies TG2 As a Potential Target in Chemo-Resistant Ovarian Cancer Posted by Paul Cacciatore on July 15, 2008
“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.”
“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 Departments of Gynecologic Oncology and Cancer Biology, and Kapil Mehta, Ph.D., professor in the Department of Experimental Therapeutics 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 information 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 significantly 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.
‘From this investigation it became clear that TG2 activates the survival pathway p13K/Akt in these tumors, explaining the adverse, resistant 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 gemcitabine 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 Excellence 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-Destruction M. D. Anderson News Release 03/20/07 An overexpressed protein protects human pancreatic cancer cells from being forced to devour themselves, 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 inflammatory 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 research 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 programmed 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.
News
University 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. For more news, visit the UCLA Newsroom and follow us on Twitter.
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