Contributions

Dr. Tibes and his Lab have contributed to several advances in cancer. Dr Tibes has been involved or provided pre-clinical data for three new drugs that were ultimately approved, thus making his research efforts truly translation to benefit cancer treatment and patients.

Proteomic Profiling in AML

My early work performed during my fellowship centered around functionally dissecting signal transduction pathways and map phospho-protein signaling in primary AML cells; with a goal of arriving at more specific targeting by novel drugs (i.e. kinase inhibitors).  As a fellow I established the Reverse Phase Protein Array Platform (RPPA) for primary AML cells at MD Anderson Cancer Center that led to several publications including the description of its’ utility for leukemia stem cells and frequerntly cited publications in this field.  Since then this platform has been extensively used to characterize AML and MDS protein signaling networks. Results from RPPA on primary AML an MDS cells have made essential contributions to several papers that led to translation into clinical trials (i.e. the 5-Azacitidine+ Birinapant trial or the 5-Azacitidine + Venetoclax (ABT-199 BCL2 trial).

Tibes R, Qiu Y, Lu Y, Hennessy B, Andreeff M, Mills GB, Kornblau SM.l. Reverse Phase Protein Array (RPPA): Validation of a Novel Proteomic Technology and Utility for Analysis of Primary Leukemia Specimens and Hematopoetic Stem Cells (HSCT). Mol Cancer Ther. 2006 Oct;5(10):2512-21. PMID: 17041095 PMCID in process

Tibes R, Kornblau SM, Qiu Y, Mousses SP, Robbins C, Moses T, Carpten JD, PI3K/AKT Pathway Activation in Acute Myeloid Leukaemias is Not Associated With AKT1 Pleckstrin Homology (PH) Domain Mutation. Br J Haematol. 2008 Feb;140(3):344-7 PMID: 18053070 PMCID: PMC3385948

*Kornblau SM, *Tibes R, et al. Functional Proteomic Profiling of Acute Myeloid Leukemias (AML) Predicts Response and Survival Outcome. Blood. 2009 Jan 1;113(1):154-64 PMID: 18840713 PMCID: PMC2951831*Equal contribution

DNA Damage Repair and Cell Cycle Checkpoint Targeting in AML

The interest for exploiting DNA damage repair and cell cycle checkpoint pathways has been longstanding ever since the first RNAi screens of AraC and the human kinome leading to the discovery of WEE1 kinase inhibition as potent sensitizer to AraC. Through RNAi functional genomics approaches we have also confirmed CHEK1 as another sensitizer to AraC. The first in leukemia clinical trial of AraC with AZD1775 (WEE1 inhibitor, formerly MK1775) is a result of my laboratory work and I am the study PI of an investigator sponsored trial (IST). For CHEK1 we showed clinical activity and sensitization to AraC, especially in hard to treat post-allogeneic transplant relapsed AML patients. We have been involved in the field of DNA/Cell cycle checkpoint targeting for other projects including several first in human trials and biomarker studies.

Tibes R, Bogenberger JM, Chaudhuri L, Hagelstrom RT, Chow D, Buechel ME, Gonzales IM, Demuth T, Slack J, Mesa RA, Braggio E, Yin HH, Arora S, Azorsa DO. RNAi screening of the kinome with cytarabine in leukemias. Blood. 2012 Mar 22;119(12):2863-72. Epub 2012 Jan 20. PMID:22267604

Chaudhuri L, Vincelette ND, Koh BD, Naylor RM, Flatten KS, Peterson KL, McNally A, Gojo I, Karp JE, Mesa RA, Sproat LO, Bogenberger JM, Kaufmann SH, Tibes R. Chk1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo. Haematologica. 2014 Apr;99(4):688-96. PMID: 24179152

Shapiro G, Tibes R, Gordon M, et al. Phase I Studies of CBP501, a G2 Checkpoint Abrogator, as Monotherapy and in Combination with Cisplatin in Patients with Advanced Solid Tumors. Clin Cancer Res. 2011 May 15;17(10):3431-42. PMID: 21220472  

Leijen S, van Geel RM, Pavlick AC, Tibes R, Rosen L, Razak AR, Lam R, Demuth T, Rose S, Lee MA, Freshwater T, Shumway S, Liang LW, Oza AM, Schellens JH, Shapiro GI. Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors. J Clin Oncol. 2016 Dec 20;34(36):4371-4380. PMID: 27601554

Webster JA, Tibes R, Morris L, Blackford AL, Litzow M, Patnaik M, Rosner GL, Gojo I, Kinders R, Wan L, Doyle LA, Huntoon CJ, Karnitz LM, Kaufmann SH, Karp JE, Smith BD. Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia. Leuk Res. 2017 Oct;61:108-116. PMID: 28957699

Novel Rational HMA and Epigenetic Combinations

A strong focus has been my translational work of finding novel rational hypomethylating agents (HMA) combinations in MDS and AML. Our laboratory was the first to describe (in abstract form at ASH 2010) that BCL-XL and BCL-2 are potent synergistic targets with 5-Azacitidine. We extended our work into showing potent synergy of ABT-199 with 5-Aza as well, providing the pre-clinical work for a trial that has shown remarkable clinical response rates to date. Our laboratory has further contributed to pre-clinical work leading to Phase 1 and 2 trials of 5-Azacitidne and the SMAC mimetic (cIAP1) birinapant in high-risk MDS patients. Clear re-sensitization was observed even in HMA refractory patients. We reported for the first time strong combination activity of 5-Aza plus the SMO inhibitor LDE225 (Vismodegib) and an IST trial has been completed. Lastly, we just published the potent interaction between CDK9 and BCL-2 inhibition which led to a company sponsored trial in AML. Thus, four novel rational combination trials with HMAs have been translated into the clinic directly from or by contributions of my laboratory. Furthermore, we have performed additional siRNA sensitizer screens with 5-Azacytidine, HDAC inhibitors and Lenalidomide results of which are currently being validated and proposal for trials are underway.

Tibes R, Choudhary A, Henrichs A, Guled S, Monzon I, Peralta L, Mousses M, Azorsa D. Identification of sensitizing targets to the hypomethylating agent 5-azacytidine in acute myeloid leukemia cells using RNAi-based functional genomics screening, blood. ASH. 2008 Nov; 112:2665.

Tibes R., Bogenberger J, Choudhary A, Monzon I, Chow D, Kiefer J, Azorsa DO. RNAi-based Identification of Novel Sensitizers to 5-Azacytidine in Myeloid Leukemias. EHA, Haematologica | 2009; 94(s2):0536

Bogenberger JM, Shi CX, Hagelstrom RT, Gonzales I, Choudhary A, Tiedemann R, Azorsa D, Stewart S, Tibes R. Synthetic lethal RNAi screening identifies inhibition of Bcl-2 family members as sensitizers to 5-Azacytidine in myeloid cells. AACR Annual Meeting, Washington, D.C. 2010. Abstract no. LB-128.

Bogenberger JM, Shi CX, Gonzales I, Tiedemann RE, Noel P, Slack JL, Mesa RA, Stewart K, Qiu YH, Coombes KR, Komblau SM, Azorsa D, Tibes R. RNAi screening identifies BCL-XL as an erythroid lineage-specific 5-azacytidine sensitizer while the BCL-2/BCL-XL/BCL-W inhibitor ABT-737 results in more universal sensitization in leukemia cells. Blood. 2011 Nov 18; 118(21):1498.

Bogenberger JM, Pierceall WE, Lena R, Munker R, Tohyama K, Sproat L, Noel P, Leis JF, Slack JL, Mesa RA, Cardone M, Tibes R. Bh3 profiling predicts 5-azacytidine response in malignant myeloid cells. Blood. 2012 Nov 16; 120(21).

Bogenberger JM, Kornblau SM, Pierceall WE, Lena R, Chow D, Shi CX, Mantei J, Ahmann G, Gonzales IM, Choudhary A, Valdez R, Camoriano J, Fauble V, Tiedemann RE, Qiu YH, Coombes KR, Cardone M, Braggio E, Yin H, Azorsa DO, Mesa RA, Stewart AK, Tibes R. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia. 2014 Aug; 28(8):1657-65. Epub 2014 Jan 23. 

Bogenberger JM, Delman D, Hansen N, Valdez R, Fauble V, Mesa RA, Tibes R. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-Azacytidine in myeloid malignancies. Leuk Lymphoma. Leuk Lymphoma. 2015 Jan;56(1):226-9.  Epub 2014 Jun 17

Carter BZ, Mak PY, Mak DC, Shi Y, Qiu Y, Bogenberger JM, Tibes R, Yao H, Coombes KR, Jacamo RO, Weng D, Burns J, McKinlay MA, Kornblau S, Andreeff M. Novel SMAC Mimetic Birinapant Induces Apoptosis in CD34+38- AML Cells and Synergizes with Demethylating Agents J Natl Cancer Inst. 2014 Feb;106(2). PMID: 24526787

SMO/Hedgehog Pathway Inhibitor and Pivotal Phase 1 and Basal Cell Cancer (BCC) Trial/Report

I treated the first patient ever with a SMO inhibitor and clinically took care of the majority of BCC patients reported in the initial NEJM publication. I remained involved in several other novel SMO/Hedgehog pathway inhibitors as well as extended work into an investigator initiated trial (IST) of 5-Azacitidine + Erismodegib in AML, MDS and MPNs.

Von Hoff D.D., LoRusso P.M., Rudin C.M., Reddy J., Yauch B., Tibes R., et al., “Safety and Efficacy of GDC-0449 Hedgehog Pathway Inhibitor in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma in a Phase I Trial”. N Engl J Med. 2009 Sep 17;361(12):1164-72.

LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ et al., Phase I trial of hedgehog pathway inhibitor GDC-0449 in patients with refractory locally-advanced or metastatic solid tumors. Clinical  Cancer Res. 2011 Feb 7.

Jimeno A, Weiss GJ, Miller WH Jr, Gettinger S, Eigl BJ, Chang AL, Dunbar J, Devens S, Faia K, Skliris G, Kutok J, Lewis KD, Tibes R, Sharfman WH, Ross RW, Rudin CM. Phase I Study of the Hedgehog Pathway Inhibitor IPI-926 in Adult Patients with Solid Tumors. Clin Cancer Res. 2013 May 15;19(10):2766-2774.

Tibes R, Al-Kali A, Oliver GR, Delman DH, Hansen N, Bhagavatula K, Mohan J, Rakhshan F, Wood T, Foran JM, Mesa RA, Bogenberger JM. The Hedgehog pathway as targetable vulnerability with 5 azacytidine in myelodysplastic syndrome and acute myeloid leukemia. J Hematol Oncol. 2015 Oct 20;8(1):114. PMID: 26483188