OMB No. 0925-0001 and 0925-0002 (Rev. 10/2021 Approved Through 09/30/2024)

NAME: Vahid Afshar-Kharghan

eRA COMMONS USER NAME (credential, e.g., agency login): VAHIDAK

POSITION TITLE: PROFESSOR

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

1. Personal Statement

I am a physician-scientist at the University of Texas M.D. Anderson Cancer Center. I have studied platelet's hemostatic and non-hemostatic functions over the past 23 years. During this time, I have established strong and productive collaborations with investigators from various scientific fields to examine the role of platelets in hemostasis, inflammation, and cancer progression. We have identified the mechanism of paraneoplastic thrombocytosis in ovarian cancer and showed that platelets increase the growth of primary tumors. Platelets impact the growth of tumors by extravasating into the tumor microenvironment (TME) and interacting with cancer cells. During this interaction, cancer cells activate platelets, and platelets increase the proliferation of cancer cells. We examined the molecular mechanisms of platelet extravasation and platelet-cancer cell interaction. In addition to the proliferation of cancer cells, we found that platelets also impact the immune milieu in the TME. We showed that platelets increase the expression of immune checkpoints in cancer and immune cells. Manipulating platelet counts or function modifies the response to immunotherapy. We showed that platelets also alter the immune profile of tumors by increasing pro-tumor B cells. Platelets enhance the migration of B cells into the tumor and increase the proliferation and maturation of B lymphocytes in the TME. We will examine the platelet molecules that mediate the interaction with B cells. We will examine the possibility of manipulating platelets to enhance the immune response to tumors (ovarian cancer, melanoma, and lung cancer) and predict and potentiate immunotherapy's effectiveness. I have highlighted our recently published manuscript on this topic.

a) Cho MS, Lee H, Gonzalez-Delgado R, Li D, Sasano T, Carlos-Alcalde W, Ma Q, Liu J, Sood AK, Afshar-Kharghan V.  Platelets Increase the Expression of PD-L1 in Ovarian Cancer, Cancers (Basel), 2022 May 19;14(10):2498, doi: 10.3390/cancers14102498.

Cho MS, Li J, Gonzalez R, Lee H, Vasquez M, He T,  He Y, Liu K, Sasano T, Nürnberg B, Sood AK, Wong STC, Afshar-Kharghan V. Platelet G-proteins mediate the pro-tumor effect of platelets in ovarian cancer. Blood Advan 5(7):1947-1951, 4/2021.

Sasano T, Gonzalez-Delgado R, Muñoz NM, Carlos-Alcade W,  Cho MS, Sheth RA, Sood AK, Afshar-Kharghan V. Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer. Journal of Thrombosis and Haemostasis 20(1):104-114, 1/2022.

Gonzalez-Delgado R, Muñoz NM, Carlos-Alcalde W, Cho MS, Lee H, Jin J, Serpas V, Gorlova O, Sheth RA, Afshar-Kharghan V. Role of circulating mitochondria in venous thrombosis in glioblastoma. Journal of Thrombosis and Haemostasis 21(8):2202-2212, 8/2023.

The list of my relevant ongoing or completed research grants is as follows:

Ongoing Research Support

2 R01 CA177909-06A1 (Contact PI: Afshar-Kharghan)  12/01/2018-11/30/2024. NCE

NIH/NCI

Title: Platelets Promote Growth of Ovarian Cancer

Goal: The primary goal of this project is to identify the mechanism of platelet extravasation into the tumor microenvironment and the effect of extravasated platelets on tumor growth.

R01 CA231141 (Contact PI: Afshar-Kharghan)               8/8/2018 – 7/31/2024 NCE

NIH/NCI

Title:  Genetics of graft-versus-host disease

Goal: The major goal of this project is to identify novel non-HLA genetic polymorphisms that increase the risk of acute graft-versus-host disease (GVHD) after an allogeneic hematopoietic stem cell transplant. We will conduct GWAS on 9500 DNA samples collected from donors and recipients by the National Marrow Donor Program (NMDP)/Center for International Blood and Marrow Transplant Research (CIBMTR) and correlate the results to the severity of GVHD.

R01 CA275762 (Contact PI: Afshar-Kharghan)               9/19/2023 – 9/18/2028

NIH/NI

Title: Novel Biomarkers Predicting Blood Clots in Ovarian Cancer

Goal: This project aims to identify the cancer-related or cancer-released factors that increase the risk of venous thrombosis in ovarian cancer.

R01 CA247917 (PI: Vijayan, Vinod)                                 03/01/2021-02/28/2025

NIH/NCI

Role: Co-Investigator

Title:  Platelet Serine/Threonine Phosphatases in Cancer Pathophysiology

Goal: The major goal of this project is to evaluate how protein phosphatase 1 alpha contributes to cancer metastasis.

B.        Positions, Scientific Appointments, and Honors
Positions

9/15-    Professor, Benign Hematology, Division of Internal Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX

4/08-9/15         Associate Professor, Benign Hematology, Division of Internal Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX

9/00-4/08         Assistant Professor, Thrombosis Research Center, Department of Medicine, Baylor College of Medicine, Houston, TX

7/98-7/00         Clinical Fellow, Department of Hematology/Oncology, Baylor College of Medicine, Houston, TX

7/97-7/98         Research Fellow, Department of Hematology/Oncology, research in molecular hematology under the supervision of José A. López, M.D., Baylor College of Medicine, Houston, TX

7/95-7/97         Postdoctoral fellowship under the supervision of José A. López, M.D, Clinical Investigator Pathway, Department of Medicine, Baylor College of Medicine, Houston, TX.

7/93-7/95         Residency in Internal Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX.

Other Experience and Professional Memberships

2016-               Member, the American Society of Clinical Investigation (ASCI)

2015-               Ad-hoc member, Hemostasis and Thrombosis (HT) study section, NHLBI, NIH

2014                Ad-hoc member, Program Project Grant Review Committee, NHLBI, NIH

2008-2014       Member, Review Committee for VA Merit Applications, Hematology subcommittee

2007                Scientific Review Committee for Special Emphasis Panel, NIDDK, NIH

2007                Ad-hoc member, Review committee for VA Medical Research Cellular and Molecular Medicine Merit Review Subcommittee (CAMM)

2006                Ad-hoc member, Review Committee for VA Merit Applications, Hematology subcommittee

2002-               Member, American Society of Hematology

2008-               Member, International Society of Haemostasis and Thrombosis

2000-               Scientific Reviewer for Journals: Blood, Circulation, Journal of Thrombosis and Hemostasis, American Journal of Hematology, Current opinion in immunology, Leukemia Research, Platelet

Academic and Professional Honors

3/2021-            McCullough Professorship for Cancer Research

2016-               Member, the American Society of Clinical Investigations (ASCI)

2010-2011       Excellence in Teaching Award, Division of Cancer Medicine Hematology/Oncology Fellowship Program, 2010-2011

7/2005             T.T. Chao Scholar, Department of Medicine, Baylor College of Medicine, Houston, TX

7/2000             Caroline Wiess Law research fund grantee, Department of Medicine, Baylor College of Medicine, Houston, TX

8/99                 Young Investigator Award from the International Society on Thrombosis and Haemostasis

4/97                 Outstanding Presentation-Basic Research award in the research symposium, Department of Medicine, Baylor College of Medicine, Houston, TX

7/96                 Excellence for Outstanding Achievement in Ambulatory Care Medicine certificate from General Medicine Clinic, Department of Medicine, Houston VA Medicine Service, Houston, TX

12/96               Travel Award from American Society of Hematology for oral presentation in the 38th annual meeting of American Society of Hematology, Orlando, Florida

7/93-7/97         Clinical Investigator Pathway, Department of Medicine, Baylor College of Medicine, Houston, TX

C.        Contributions to Science

1) Platelet and cancer. Paraneoplastic thrombocytosis is a common finding in cancer patients and is associated with worsened clinical outcomes. About one-third of patients with ovarian cancer have platelet counts above limited upper normal at diagnosis. We were interested in finding out the mechanism of paraneoplastic thrombocytosis and the effect of platelets on cancer progression. Our initial observation that a murine model of ovarian cancer develops thrombocytosis was a breakthrough that provided us with an animal model for paraneoplastic thrombocytosis. We identified that ovarian cancer cells secrete IL6 that enhances the production of thrombopoietin from the liver, ultimately causing thrombocytosis. We discovered that platelets increase the growth of the primary tumors in ovarian cancer by increasing cancer cell proliferation and promote metastasis by reducing anoikis. Platelets also reduce the sensitivity of cancer cells to chemotherapy and increase their resistance to antiangiogenic reagents. We identified P2Y12 receptors on platelets, and TGFβ1 receptors on cancer cells are important in platelet-cancer cell interaction and ovarian cancer growth. We have shown that platelets extravasate into the tumor microenvironment and have optimized advanced imaging studies, including cryo-EM, whole-slide imaging, 2-photon microscopy, and CARS to study platelet morphology and extravasation into tumors. I have provided a list of a few of our published manuscripts.

a) Hu Q, Hisamatsu T, Hammerle M, Cho MS, Pradeep S, Rupaimoole R, Rodriguez-Aguayo C, Lopez-Berestein G, Wong ST, Sood AK, Afshar-Kharghan V. Role of platelet-derived Tgfβ1 in the progression of ovarian cancer. Clin Cancer Res. 23:5611-5621, 2017. PMID: 28611202

b) Cho MS, Noh K, Haemmerle M, Li D, Park H, Hu Q, Hisamatsu T, Mitamura T, Mak SLC, Kunapuli S, Ma Q, Anil K. Sood AK and Vahid Afshar-Kharghan V. Role of ADP receptors on platelets in the growth of ovarian cancer. Blood. 130:1235-1242. 2017. PMID:28679740

c) Haemmerle M, Taylor ML, Gutschner T, Pradeep S, Cho MS, Sheng J, Lyons Y, Nagaraja A, Wen Y, Dood R, Mangala L, Hansen J, Rupaimoole R, Gharpure K, Rodriguez-Aguayo C, Yim SY, Lee J-S, Ivan C, Hu W, Lopez-Berstein G, Wong S, Karlan S, Levine S, Liu J, Afshar-Kharghan V, and Sood AK. Platelets reduce anoikis and promote metastasis by activating YAP1 signaling. Nat Commun. 8:310. 2017. PMID:28827520

d) Cho MS, Li J, Gonzalez-Delgado R, et al. The effect of platelet G proteins on platelet extravasation and tumor growth in the murine model of ovarian cancer. Blood Adv. 5(7):1947-1951. 2021. PMID: 33821990

2) Complement and cancer. We identified that ovarian cancer cells secrete complement proteins into the tumor microenvironment, and reduction of C3 and C5 production by cancer cells inhibited tumor growth. We showed that many cancer cells, including ovarian cancer cells, express anaphylatoxin receptors and respond to complement activation by an increase in cell proliferation. These findings pointed toward the presence of an autocrine loop involving complement activation in the tumor microenvironment that promotes tumor growth. The next question was to identify the mechanism of overexpression of C3 in ovarian cancer cells. We showed that TWIST1 positively regulates C3 expression, and anaphylatoxin C3a participates in the TWIST1-mediated epithelial-mesenchymal transition. These exciting results led us to believe that complement activation inside a tumor is an unappreciated and important factor that determines the aggressiveness of a malignancy. 

a) Cho MS, Vasquez HG, Rupaimoole R, Pradeep S, Wu S, Zand B, Han H-D, Rodriguez-Aguayo C, Bottsford-Miller J, Huang J, Miyake T, Dalton H, Ivan C, Baggerly K, Lopez-Berestein G ,. Sood AK, and Afshar-Kharghan V. Autocrine effects of tumor-derived complement. Cell Reports. 6:1085-95. 2014. PMID:24613353

b) Cho MS, Rupaimoole R, Choi HJ, Noh K, Chen J, Hu Q, Sood AK, Afshar-Kharghan V. Complement component 3 is regulated by TWIST1 and mediates epithelial-mesenchymal transition. J Immunol. 196:1412-8. 2016. PMID:26718342

c) Afshar-Kharghan V. The role of the complement system in cancer. J Clin Invest. 127(3):780-789. 2017. PMID: 28248200.

3) Complement and platelet: After finishing my fellowship, I joined the Baylor College of Medicine Thrombosis Research Section as a junior faculty. To embark on my independent research career, I chose to study the interactions between the complement proteins and platelets. There were several reasons behind this decision. First, many complement disorders are associated with thrombosis, and I could not find a satisfactory explanation for this association. Second, the effect of complement activation endproducts on platelets was studied in the past, but the impact of platelet activation on the complement system was relatively unknown. Third, the complement system shared many similarities to the coagulation system, and I hypothesized that similar to the coagulation proteins, complement proteins interact with platelets. I embarked on these studies before the discovery of complement mutations in patients with the atypical hemolytic uremic syndrome (aHUS) and before the availability of an anti-complement reagent in clinical practice. My studies showed that platelet activation activates the alternative complement pathway on the surface of platelets. This study was followed by several other groups establishing the role of platelets in activating classic and lectin complement pathways. 

a) Del Conde I, Cruz MA, Zhang H, López JA, and Afshar-Kharghan V: Platelet Activation leads to Activation and Propagation of the Complement System: a link between Thrombosis and Inflammation. Journal of Experimental Medicine. 201:871-9. 2005. PMID:15781579

b) Mnjoyan z, Li J, Afshar-Kharghan V. Factor H binds to platelet integrin allbb3. Platelets. 19:512-9. 2008. PMID:18979363

c) Gushiken FC, Han H, Li J, Rumbaut RE, Afshar-Kharghan V. Abnormal platelet function in C3 deficient mice. Journal of Thrombosis and Haemostasis. 7: 865-70. 2009. PMID:19291167

4) Complement and thrombotic microangiopathies. After my studies on the interactions between complement proteins and platelet, I focused on the other interactions between the complement system and hemostatic factors. I was intrigued with the observation that many patients with a clinical picture very similar to Thrombotic Thrombocytopenia Purpura (TTP) have only a mild reduction in their ADAMTS13 activity. Considering that complement mutations cause aHUS, thrombotic microangiopathy very similar to TTP, I hypothesized that some patients with mild deficiency of ADAMTS13 develop thrombotic microangiopathy in the presence of complement dysregulation (a two-hit scenario). We detected complement dysregulation in several patients with a clinical diagnosis of TTP, and we found that many patients with a diagnosis of aHUS had a mild-moderate ADAMTS13 deficiency. To identify whether there is an interaction between complement and VWF regulation, we studied the interactions between VWF and complement regulatory proteins and recognized that there is crosstalk between the complement system and VWF/ADAMTS13. 

a) Feng S, Kroll MH, Nolasco L, Moake J, Afshar-Kharghan V. Complement activation in thrombotic microangiopathies. Br J Haematol. 160: 404-6. 2013. PMID:18979363

b) Feng S, Eyler SJ, Zhang Y, Maga T, Nester CM, Kroll MH, Smith RJ, Afshar-Kharghan V. Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome. Blood. 122:1487-93. 2013. PMID:23847193

c) Feng S, Liang X, Cruz MA, Vu H, Zhou Z, Pemmaraju N, Dong JF, Kroll MH, Afshar-Kharghan V. The interaction between Factor H and Von Willebrand Factor. PLOS ONE. 8:e73715. 2013. PMID:23991205

d) Feng S, Liang X, Kroll MH, Chung DW, and Afshar-Kharghan V. Von Willebrand Factor is a cofactor in complement regulation. Blood. 125:1034-7. 2015. PMID:25395424

5) Complement activation in the complications after allogeneic bone marrow transplantation. I have studied the effect of complement activation in the pathogenesis of the alloimmune response after allogeneic hematopoietic stem cell transplantation. I have closely collaborated with Dr. Qing Ma, a co-investigator in the current RO1 application, on this project. Graft-versus-host disease is an alloimmune response mediated by donor's T cells against antigen-presenting cells from recipients. We found that complement activation plays an important role in the development and determining the severity of GVHD. Complement deficient mice do not develop GVHD after bone marrow transplant, and a complement inhibitor prevented the proliferation of alloreactive T cells in mixed lymphocyte reactions. These studies have resulted in several publications, funding of our R21 application, and perhaps more importantly, in a pilot multi-institutional clinical trial in patients with severe GVHD.

a) Ma Q, Li D, Nurieva R, Patenia R, Bassett R, Cao W, Alekseev AM, He H, Molldrem JJ, Kroll MH, Champlin RE, Sale GE, Afshar-Kharghan V. Reduced graft-versus-host disease in C3-deficient mice is associated with decreased donor Th1/Th17 differentiation. Biol Blood Marrow Transplant. 18:1174-81. 2012. PMID:22664751

b) Ma Q, Li D, Carreño R, Patenia R, Tsai KY, Smith M, Alousi AM, Champlin RE, Sale GE, and Afshar-Kharghan V . Complement component C3 mediates Th1/Th17 polarization in human T cell activation and Cutaneous Graft-versus-Host Disease. Bone Marrow Transplant. 49:972-6. 2014. PMID:24777193

For a complete list of my publications, please use the following URL:‌

http://www.ncbi.nlm.nih.gov/sites/myncbi/vahid.afshar-kharghan.1/bibliography/45816058/public/?sort=date&direction=ascending