Mathew Lab

The Mathew laboratory is focused on the investigation of epithelial-stromal interactions that drive the metastatic progression of human malignancies and the development of novel therapeutics that target these mechanisms. Our major focus has been on prostate cancer and its progression to the highly-conserved phenotype of bone metastases. Our laboratory at Tufts Medical Center has identified a seed-and-soil mechanism involving integrin cooperativity in tumor-stromal interactions of prostate cancer and developed a proprietary bispecific antibody to target this cooperative biology (Joshi Cell Adh Migr 2016, Joshi et al, AACR 2018). We have traced survival pathways mediated by integrins in prostate cancer cells to the BCL-XL protein and have defined synthetic lethality in PTEN-deficient prostate cancer cells with the combination of PI3K/AKT and BCL-XL inhibition (Ren et al, MCR 2016; Ren et al, AACR 2018).  Our long-term goal is to translate these advances to the clinic in prostate cancer and other malignancies which share this thematic biology. 

Prostate cancer and bone metastases; integrin cooperativity in epithelial-stromal interactions; synthetic lethality in PTEN-deficient prostate cancer; clinical translation of experimental therapeutics in prostate cancer.  

Paul Mathew, MD is a faculty member in the Department of Hematology-Oncology at Tufts Medical Center from 2009-present. He is principally responsible for clinical care of all genitourinary malignancies (prostate, kidney, testis, penile and bladder cancer) and experimental therapeutics in these tumors at Tufts Medical Center. Dr Mathew completed his Internal Medicine Residency at Cook County Hospital, Chicago IL and Hematology-Oncology Fellowship at Mayo Clinic, Rochester MN. His prior faculty position was in the Division of Genitourinary Medical Oncology at MD Anderson Cancer Center, Houston, 2001-2009.

Staff members:

Paul Mathew, MD
Raghav Joshi, BSc
Wenying Ren, PhD

Prostate cancer and experimental therapeutics

1. Uehara H, Kim SJ, Karashima T, Shepherd DL, Fan D, Tsan R, Killion JJ, Logothetis C, Mathew P, Fidler IJ. Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst 2003;95:458-70

2. Mathew P, Fidler IJ, Logothetis CJ. Combination docetaxel and platelet-derived growth factor receptor inhibition with imatinib mesylate in prostate cancer. Semin Oncol 2004;31:24-9

3. Mathew P, Thall PF, Jones D, Perez C, Bucana C, Troncoso P, Kim SJ, Fidler IJ, Logothetis C. Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: a modular phase I trial in androgen-independent prostate cancer. J Clin Oncol 2004;22:3323-3329

4. Kim SJ, Uehara H, Yazici S, He J, Langley RR, Mathew P, Fan D, Fidler IJ. Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer. Cancer Res 2005;65:3707-15

5. Kim SJ, Uehara H, Yazici S, Busby JE, Nakamura T, He J, Maya M, Logothetis C, Mathew P, Wang X, Do KA, Fan D, Fidler IJ. Targeting platelet-derived growth factor receptor on endothelial cells of multidrug-resistant prostate cancer. J Natl Cancer Inst 2006;98:783-93

6. Mathew P, Logothetis CJ, Dieringer PY, Chen I, Pagliaro LC, Bekele BN, Zhou X, Daliani DD. Thalidomide/estramustine/paclitaxel in metastatic androgen-independent prostate cancer. Clin Genitourin Cancer 2006;5:144-9

7.Rodney A, Dieringer P, Mathew P, Jonasch E, Tannir N, Pagliaro LC. Phase II study of capecitabine combined with gemcitabine in the treatment of androgen-independent prostate cancer previously treated with taxanes. Cancer 2006;106:2143-2147

8. Kantoff PW, Beer TM, D'Amico AV, Dipaola RS, Eisenberger MA, Hussain MH, Kelly WK, Mathew P, Morris MJ, Ryan CJ, Sandler HM, Thompson IM, Carroll PR. Innovations and challenges in prosate cancer: summary statement for the 6th Cambridge Conference. J Urol 2007;178 (3 Pt 2):S5-8

9. Mathew P, Thall PF, Bucana CD, Oh W, Morris MJ, Jones DM, Johnson MM, Wen S, Pagliaro L, Tannir NM, Tu S-M, Meluch AA, Smith L, cohen L, Kim S-J, Troncoso P, Fidler IJ, Logothetis C. Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases. Clin Cancer Res 2007;13:5816-24

10. Mathew P, DiPaola R. Taxane refractory prostate cancer. J Urol 2007;178 (3) Pt. 2):S36-41

11. Mathew P. Imatinib and the neoplastic bone microenvironment. Blood 2008;111:2495-2496

12. Li ZG, Yang J, Vasquez ES, Rose D, Vakar-Lopez F, Mathew P, Lopez A, Logothetis CJ, Lin S-H, Navone NM. Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone. Oncogene 2008;27:596-603

13.Lin S-H, Lee Y-C, Choueir MB, Wen S, Mathew P, Ye X, Do KA, Navone NM, Kim J, Tu SM, Yu-Lee LY, Logothetis CJ. Soluble ErbB3 levels in bone marrow and plasma of men with prostate cancer. Clin Cancer Res 2008;14:3729-36

14. Li Zhi Gang, Mathew P, Yang J, Starbuck MW, Zurita AJ, Liu J, Sikes C, Multani AS, Efstathiou E, Lopez A, Wang J, Fanning TV, Prieto VG, Vikas K, Vazquez ES, Troncoso P, Raymond AK, Logothetis CJ, Lin S-H, Maity S, Navone N. Androgen Receptor-Negative Human Prostate Cancer Cells Induce Osteogenesis through FGF9-Mediated Mechanisms. Journal of Clinical Investigation. 2008;118(8):2697-710

15.Mathew P, Thall PF, Wen S, Bucana C, Jones D, Horne C, Oh WK, Morris MJ, Lee Y-C, Logothetis CJ, Lin S-W, Fidler IJ. Dynamic change in phosphorylated platelet-derived growth factor receptor in peripheral blood leucocytes following docetaxel therapy predicts progression-free and overall survival in prostate cancer. British Journal of Cancer 2008; 99:1426-1432.

16. Morris MJ, Basch EM, Wilding G, Hussain M, Carducci MA, HIgano C, Kantoff P, Oh WK, Small EJ, George D, Mathew P, Beer TM, Slovin SF, Ryan C, Logothetis C, Scher HI. Department of Defense Prostate Cancer Clinical Trials Consortium: A New Instrument for Prostate Cancer Clinical Research. Clin Genitourin Cancer. 2009;7:51-7

17. Mathew P, Thall P, Pisters LL, Wen S, Fidler IJ, Langley RR, Williams DL, Horne E, Pettaway CA, Wood CG, Oborn CJ, Papadopoulos J. Neoadjuvant Platelet-derived growth Factor Receptor Inhibitor Therapy Combined with Docetaxel and Androgen Ablation for High-risk Localized Prostate Cancer. Journal of Urology 2009;181:81-7.

18. Rosenberg JE, Ryan CJ, Weinberg V, Smith DC, Hussain M, Beer TM, Ryan CW, Mathew P, Pagliaro L, Harzstark AL, Sharib J, Small EJ. A phase I study of ixabepilone, mitoxantrone and prednisone in patients with metastatic castration resistant prostate cancer treated with docetaxel-based therapy: a study of the Department of Defense Prostate Cancer Clinical Trials Consortium. J Clin Oncol 2009;27:2772-2778

19. Tu SM, Mathew P, Wong FC, Jones D, Johnson MM, Logothetis CJ. Phase I study of concurrent weekly docetaxel and repeated 153sm-Lexidronam in patients with castration-resistant metastatic prostate cancer. J Clin Oncol 2009;27:3319-3324

20. Taplin ME, Regan MM, Ko YJ Bubley GJ, Duggan SE, Werner L, Beer TM, Ryan CW, Mathew P, Tu SM, Denmeade SR, Oh WK, Sartor O, Mantzoros CS. Rittmaster R, Kantoff PW, Balk SP. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res 2009;15:7099-7105.

21.Efstathiou E, Abrahams NA, Tibbs RF, Wang X, Pettaway CA, Pisters LL, Mathew P, Do KA, Logothetis CJ, Troncoso P. Morphological characterization of preoperatively treated prostate cancer: toward a post-therapy histologic classification. Eur Urol 2009;Oct 17 (Epub).

22.Mathew P, Tannir N, Tu SM, Carter C, Bekele N, Pagliaro L. A modular Phase I study of lenalidomide and paclitaxel in metastatic castration-resistant prostate cancer following prior taxane therapy. Cancer Chemotherapy and Pharmacology 2010;65:811-815

23.Morita S, Thall PF, Bekele N, Mathew P. A Bayesian hierarchical mixture model for platelet-derived growth factor receptor phosphorylation to improve estimation of progression-free survival in prostate cancer. Journal of Royal Statistical Society, Series C 2010;59:19-34

24.Bradley DA, Daignault S, Ryan CJ, Dipaola RS, Cooney KA, Smith DC, Small E, Mathew P, Gross ME, Stein MN, Chen A, Pienta KJ, Escara-Wilke J, Doyle G, Al-Hawary M, Keller ET, Hussain M. Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium. Invest New Drugs. 2011;29:1432-40. Erratum: Invest New Drugs 2011;29;1517-8.

25.Aljumaily R, Mathew P. Optimal management of prostate cancer and bone metastases. Curr Oncol Reports 2011;13:222-230.

26.Mathew P, Tannir N, Tu SM, Wen S, Guo CC, Marcott V, Bekele BN, Pagliaro L. Accelerated disease progression in prostate cancer and bone metastases with platelet-derived growth factor receptor inhibition: observations with tandutinib. Cancer Chemotherapy and Pharmacology 2011;68:889-96

27.Mathew P, Wen S, Morita S, Thall P. Placental growth factor and soluble c-kit receptor dynamics characterize the cytokine signature of imatinib in prostate cancer and bone metastases. Journal of Interferon and Cytokine Research 2011;31:539-544

28.Lin J, Zahurak M, Beer TM, Ryan CJ, Wilding G, Mathew P, Morris M, Callahan JA, Gordon G, Reich SD, Carducci MA, Antonarakis ES. A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer. Urol Oncol 2011 Aug 2 [Epub ahead of print]

29.Araujo J, Mathew P, Armstrong A, Posadas E, Lonberg M, Gallick G, Trudel G, Paliwal P, Agarwal S, Logothetis C. Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a Phase 1/2 Study. Cancer 2012; 118:63-71

30.Zurita AJ, George DJ, Shore ND, Liu G, Wilding G, Hutson TE, Kozloff M, Mathew P, Harmon CS, Wang SL, Chen I, Chow Maneval E, Logothetis CJ. Sunitinib in combination with docetaxel and prednisone in chemotherapy-naïve patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. Annals of Oncology 2012;23:688-694

31.Dahabreh IJ, Chung M, Balk EM, Yu WW, Mathew P, Lau J, Ip S. An evidence review of active surveillance in men with localized prostate cancer. Annals of Internal Medicine 2012 2012;156:582-90

32.Brooks C, Bridges K, Sheu T, Mason K, Kuban D, Mathew P, Meyn R. Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer. Radiation Oncology 2012, 7:154. doi: 10.1186/1748-717X-7-154

33.Corn PG, Song D, Heath E, Maier J, Meyn R, Kuban D, DiPetrillo T, Mathew P. Sunitinib plus hormone ablation and radiation therapy for patients with high-risk localized prostate cancer: results from a multi-institutional phase 1 study. International Journal of Radiation Oncology Biology and Physics 2013;86:540-545

34.Rosenberg A, Mathew P. Imatinib and prostate cancer: lessons learned from targeting the platelet-derived growth factor receptor. Expert Opin Invest Drugs 2013;22:787-794

35.Aparicio AM, Harzstark A, Corn PG, Wen S, Araujo J, Tu SM, Pagliaro L, Kim J, Millikan RE, Ryan CJ, Tannir NM, Zurita A, Mathew P, Arap W, Troncoso P, Thall P, Logothetis CJ. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res 2013;19:3621-3630

36.Mathew P. The bifunctional role of steroid hormones: implications for therapy in prostate cancer. Oncology (Williston Park) 2014;28:397-404

37.Bilen MA, Johnson MM, Mathew, P, Pagliaro LC, Araujo JC, Aparicio A, Corn PG, Tannir NM, Wong FC, Fisch MJ, Logothetis CJ, Tu SM. A randomized phase II study of bone-targeted therapy containing strontium-89 in advanced castrate-sensitive prostate cancer. Cancer 2015;121:69-76

38.Mandelin J, Cardo-Vila M, Driessen WH, Mathew P, Navone NM, Lin SH, Logothetis CJ, Rietz AC, Dobroff AS, Proneth B, Sidman RL, Pasqualini R, Arap W. Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors. Proc Natl Acad Sci USA 2015;112:3776-3781

39.Joshi R, Goihberg E, Ren W, Pilichowska M, Mathew P. Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin. Cell Adhesion and Migration 2016, Aug 11:1-11. DOI: 10.1080/19336918.2016.1212139, Online

40.Ren W, Joshi R, Mathew P. Synthetic lethality in PTEN-mutant prostate cancer is induced by combinatorial PI3K/AKT and BCL-XL inhibition. Molecular Cancer Research 2016 14:1176-1181. Epub 2016 Sep 2

41.Ferrara F, Staquicini DI, Driessen WH, D'Angelo S, Dobroff AS, Barry M, Lomo LC, Staquicini FI, Cardó-Vila M, Soghomonyan S, Alauddin MM, Flores LG 2nd, Arap MA, Lauer RC, Mathew P, Efstathiou E, Aparicio AM, Troncoso P, Navone NM, Logothetis CJ, Marchiò S, Gelovani JG, Sidman RL, Pasqualini R, Arap W. Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer Proc Natl Acad Sci U S A. 2016 Oct 24. pii: 201615400.

42.Mathew P, Hachem H, Han P. The Mirage and the Quicksand: Navigating Prostate Cancer Screening in the Real-World of Primary Care. JAMA Oncol 2018;4:453-454

43.Lee L, Ali S, Genega E, Reed D, Sokol E, Mathew P. Aggressive-Variant Microsatellite-Stable POLE Mutant Prostate Cancer With High Mutation Burden and Durable Response to Immune Checkpoint Inhibitor Therapy JCO Precision Oncology 2018;2:1-8

Abstracts:

1.Joshi R, Ren W, Mathew P. Superior targeting of tumor-stromal interactions and endothelial migration with a bispecific antibody to α5 and αv integrins Proceedings of the Annual Association of Cancer Research 2018, Chicago, IL.

2.Ren W, Joshi R, Mathew P. A potent BH3 mimetic targeting BCL-XL induces apoptosis regulated by PTEN loss and integrin alpha 5 in prostate cancer cells Proceedings of the Annual Association of Cancer Research 2018, Washington D.C.

3.Joshi R, Ren W, Mathew P. MEK signaling marks a subgroup of PTEN-deficient tumors with resistance to synthetic lethality with PI3K/AKT and BCL-XL inhibition. Proceedings of the Annual Association of Cancer Research 2017, Washington D.C.

4.Flores JP, Mathew P. Combination therapy with enzalutamide and the poly (ADP-ribose) polymerase-1 (PARP1) inhibitor niraparib in castration-resistant prostate cancer (CRPC): HCRN GU 14-202, J Clin Oncol 34, 2016 (suppl; abstr TPS5095)

5.Ren W, Joshi R, Mathew P. Synergistic apoptosis induced by combined PI3 kinase and bcl-xl inhibition in genotypic subsets of prostate cancer is attenuated by a feedback signaling loop via the alpha-5 integrin. American Association of Cancer Research Annual Meeting 2016, New Orleans. Abstract #5091

6. Joshi R, Goihberg E, Pilichowska M, Mathew P. The interaction of epithelial α5β1 integrin and stromal fibronectin is a candidate seed-and-soil mechanism in prostate cancer and bone metastases. American Association of Cancer Research Annual Meeting 2015, Philadelphia. Abstract #2378

To contact the Mathew Lab, please email Paul Mathew at pmathew@tuftsmedicalcenter.org