Research

Novel CAR T Cell/NK Cell Based Therapies for Pancreatic and Ovarian Cancers

Pancreatic and ovarian cancers are relatively resistant to chemotherapy and typically diagnosed at an advanced stage, thereby precluding surgical resection and underscoring the need for novel therapies. One promising approach is the utilization of chimeric antigen receptor (CAR) T cell-based technology, which has ushered in a new era in cancer immunotherapy especially in hematological malignancies. CARs are genetically engineered simulated receptors expressed on T cells containing an extracellular single chain fragment variable (scFv) antibody fragment linked to intracellular T cell activation domain. 

Often known as a “living drug,” CAR T cells directly recognize tumor-specific antigen via scFv and kill tumor cells. Since this process circumvents the need for dendritic cell mediation in mounting immune responses, which often suffers from tumor-induced inhibition, it has revolutionized cancer immunotherapy. In other words, the extraordinary success of this therapy has been attributed to its ability to bypass tumor-imposed immune-inhibitory mechanisms. 

We have previously demonstrated in vitro killing of BxPC-3 pancreatic cancer cell-line and SKOV-3 ovarian cancer cell-line using autologous CAR T cells targeting tumor-specific antigen, mesothelin, generated via lentiviral transduction using conventional DNA. However, it has several important limitations as follows: 

1. Autologous T cell preparation is patient-specific, time consuming and labor intensive. 
2. Lentiviral vectors preferentially integrate into transcriptionally active chromosomal sites thus increasing the chances of insertional mutagenesis. 
3. Use of conventional DNA vector electroporation to avoid lentiviral vectors expresses unwanted antibiotic resistance genes and further triggers inflammatory responses due to the presence of bacterial unmethylated CpG. 
4. CAR T cell activity in pancreatic and ovarian cancers in clinical settings, in vivo, is inhibited by immunosuppressive tumor milieu. 

We developed two CAR related projects to address the above limitations. They are described below.

Project 1: “Off-the-shelf” Cellular Immuno-Therapy for Pancreatic and Ovarian Cancers

We have developed CAR therapy using bone marrow-derived primary natural killer (NK) cells as an alternative to autologous T cells which can be maintained as a continuously expandable off-the-shelf allogeneic therapy. We used sleeping beauty (SB) transposons, mobile genetic elements that are an alternative system for lentiviral transduction. SB transposons contain mesothelin scFv flanked by inverted terminal repeats enabling chromosomal integration. SB transposon chromosomal integration is without any preference for active transcriptional units, thus decreasing the risks of insertional mutagenesis. We further introduced novel minicircle (MC) plasmid technology in place of conventional DNA plasmids. MCs are devoid of redundant bacterial elements such as antibiotic resistant genes and unmethylated CpG. Being much smaller in size they are more efficient in entering cells. 

Thus, using modified natural killer cell-line (NK-92) to electroporate SB/MC mesothelin-CAR plasmid vector, we developed an allogeneic off-the-shelf therapy overcoming the limitations associated with lentiviral transduction. We demonstrated efficient killing of both pancreatic and ovarian cancer cells in vitro with an enhanced mesothelin-CAR engraftment. This has the potential to the improve the clinical safety profile of CAR T cell therapy by eliminating both viral and bacterial concerns while simultaneously increasing engraftment and cancer cell cytotoxicity.

Project 2: Blocking Inhibitory Cytokines in the Tumor Microenvironment of Pancreatic and Ovarian Cancers Potentiates Mesothelin-Chimeric Antigen Receptor NK-92MI Activity

We have previously demonstrated that mesothelin-CAR T cells kill both pancreatic and ovarian cancer cells in vitro. However, the efficacy of CAR T cell therapy for pancreatic and ovarian solid tumor treatment in vivo has not yet been successful. Solid tumors create an immune suppressive milieu in their tumor microenvironment (TME) consisting of inhibitory cytokines such as IL-10 and TGF-β secreted by regulator T cells (Tregs). IL-2 is known to protect the functional ability of T cells to overcome the negative effects of the TME. The NK-92MI cell line, which is derived from natural killer (NK) cells but genetically modified to secrete IL-2, can be utilized as part of a CAR NK cell treatment strategy to localizing IL-2 intratumorally. 

The pivotal challenge for the CAR T cell therapy against solid tumors such as pancreatic and ovarian cancers is the immunosuppressive TME that interferes with T cell activity. We posit that the blocking of IL-10 and TGF-β while producing immune-protective cytokines such as IL-2, may result in more effective CAR T and CAR NK cell therapy.

Using pancreatic (BKPC-3) and ovarian (SKOV-3) tumor-conditioned medium and patient-derived malignant ascites simulating the in vivo conditions, we can assess the effect of the TME and its reversal via depletion of IL10/TGF-β on mesothelin-CAR-NK cell cytotoxic  activity. Our approach has led to the establishment of an ex vivo system for testing various vaccine candidates against pancreatic and ovarian cancers. 

We have demonstrated a significant reversal of TME-mediated inhibition of mesothelin CAR-NK cell activity by antibody/siRNA mediated depleting IL10/TGF-β. This has been achieved with mesothelin-CAR T cells in autologous setting and more efficiently with an allogeneic off-the-shelf IL-2 secreting mesothelin-CAR-NK-92MI. This has potential for more effective clinical translation of mesothelin-engrafted CAR T cells or NK cells. 

We are in the process of deciphering various signaling pathways; if successful, our results will facilitate the development of therapeutic modalities that are non-overlapping and potentially synergistic with conventional treatment.

Combating COVID-19 

Caused by the Infection of SARS-CoV-2

A novel highly infectious SARS-CoV-2 first appeared at Wuhan, China, in December 2019 causing coronavirus disease 2019 (COVID-19). Now, a global pandemic spreading at an unprecedented speed resulting in 200 million cases and 5 million deaths. In the pathogenesis of COVID-19 pneumonia, excessive production of IL-6 often termed as cytokine storm is regarded as a key driver of severe lung damage leading to death in severe cases. Though large populations are vaccinated in developed countries, much of the remote parts of the world is still unvaccinated. Protection of the present-day vaccines has been shown to be waning over the time indicating the need for continuous supply of the vaccines. Furthermore, the virus has been shown to mutate frequently and the effectiveness of the vaccines against newly emerging more virulent forms of the virus is limited.  FDA approved vaccines in the market, if they are safer, then they are not stable at room temperature, if they can be stored at room temperature and easily deployable, then they fall short of the efficiency with safety concerns. This underscores the need for novel vaccines that are stable at room temperature, easily manufactured/deployable and neutralize emerging mutant viruses. 

Present-day prophylactic vaccines have been greatly successful in targeting SARS-CoV-2 cell-surface Spike protein that is crucial for cell-entry. We introduced modifications in the coding sequence of Spike protein such as deactivation of Furin cleavage along with stabilization mutations keeping it as more antigenic prefusion state. Further we introduced six mutations addressing most of the present-day variants of the SARS-CoV-2, making our vaccine effective against emerging variants. A successful vaccine for should elicit both humoral and cell-mediated immune responses to prevent infection and to effectively clear the virus from the cells.  Nucleic acid vaccines such as DNA- and mRNA-based vaccines activate both the arms of immune responses and are safe compared with other vaccine platforms. DNA-based vaccines need to be targeted to the nuclei of cells, as a result, have lower immunogenicity requiring multiple immunizations/adjuvants, but are easy to manufacture, transport and store. mRNA vaccines, on the other hand expressed within the cytoplasm without having to enter nuclei, thus more efficient than DNA vaccines, but requiring ultra-cold temperatures for storage with relatively higher manufacturing costs. 

To combat the threats arising from the newly emerging and more infectious variants of SARS-CoV-2, we have developed 2 state-of-art vaccines and 1 antibody drug to alleviate cytokine storm related symptoms of hospitalized patients. 

Minicircle DNA Vaccine

Traditional plasmid-DNA vaccines are safe without the need for specialized cold storage equipment, particularly easy for transport and storage for low-income countries. However, the plasmid-DNA, apart from the eukaryotic Spike expression cassette, also consists of prokaryotic bacterial elements. Although these bacterial elements such as origin of replication and antibiotic resistance genes required for the propagation of the plasmid-DNA, they cause an unwanted innate immune response limiting the duration of the Spike expression. Further there are safety concerns such as the dissemination of antibiotic resistance genes. Minicircle-DNA is an emerging novel technology that overcomes these drawbacks retaining only eukaryotic Spike expression cassette without prokaryotic bacterial elements. Minicircle-DNA is generated by adding recombination sites between the eukaryotic cassette and the prokaryotic bacterial backbone which is called Parental-DNA plasmid. The Parental-DNA plasmid thus generated is transformed into an arabinose inducible minicircle generating strain of E. coli. Arabinose induction results in the production of two plasmids, one with prokaryotic bacterial backbone that is degraded and the other is non-replicative Minicircle-DNA plasmid that is purified and used as vaccine. We used this novel technology with modified, stabilized, and mutant Spike as eukaryotic expression cassette for Minicircle-DNA vaccine. This novel Minicircle-DNA vaccine devoid of prokaryotic elements with added safety, increases the duration of immune response with higher effective dose and are easily transfected/traveled into the nucleus of target cells.

Messenger RNA (mRNA) vaccine

Self-amplifying mRNA (SARNA) vaccines ensues enhanced and prolonged antigen expression with lower doses for immunization. SARNA is based on alphavirus genome where the structural genes are replaced by SARS-CoV-2 modified Spike gene. It also encodes RNA dependent RNA polymerase responsible for mRNA amplification. SARNA vaccines offer several advantages such as rapid development, safe delivery of immunogen and intrinsic adjuvant effect. Vaccine production based on mRNA platforms uses cell-free in vitro transcription without the need for expensive fermentation units. mRNA thus produced is encapsulated in lipid nanoparticles for delivery of the immunogen into the cytoplasm of cells. 

Tocilizumab biosimilar to inhibit lung damage

Cytokine storm, a phenomenon of excessive release of large amounts of pro-inflammatory cytokines including but not limited to IL-6, associated with impaired alveolar-capillary oxygen diffusion in lungs of COVID-19 hospitalized patients causing multiple organ dysfunction. IL-6-mediated cytokine storm initiated by binding to its receptor on the cell membrane. Tocilizumab is a patent expired humanized anti-IL-6 receptor antibody, binds to the receptor and blocks IL-6 signal transduction. Remarkable beneficial effects of IL-6 blockade therapy using tocilizumab has been observed in severe COVID-19 hospitalized patients. We have developed and purified Tocilizumab biosimilar to be used for ongoing research project on chimeric antigen receptor (CAR) T-cell therapy that we are repurposing for COVID-19 therapy. 

In vitro evaluation of the vaccines drug is being conducted in fibroblast, macrophage, and mast cell lines as they are usually found in the dermis, the site of immunization. We are assessing the effect of Tocilizumab biosimilar in lymphocytes and in non-small cell lung cancer cell line, A549. In vivo safety and immunogenicity will be conducted in hACE2 mouse model. 

Team

Ramesh Babu Batchu, M.Phil., Ph.D.

Title: Associate Professor, Daland Fellow

Michael & Marian Ilitch Department of Surgery 

Wayne State University School of Medicine (WSUSOM)

4201 St. Antoine Avenue, Detroit, MI 48201

Office Address: Scott Hall, Room # 6228, 540 E Canfield St, WSUSOM, Detroit, MI 48201. 

Office Telephone: (313) 577-5315.

Email: rbatchu@med.wayne.edu

Specialty: Pancreatic, Ovarian cancers and Multiple Myeloma

Clinical Interest: Immunotherapy

Research Interest: Chimeric Antigen Receptor (CAR) T cell therapy, COVID-19 vaccines

Education

M.Sc., University of Hyderabad, Hyderabad, India

M.Phil., Ph.D., Jawaharlal Nehru University, New Delhi, India.

Post-doctoral/Instructor: University of Arkansas, Little Rock, AR., Harvard Medical School, Boston, MA.

_________________________________________________________________________________ 

Donald W. Weaver, M.D.

Title: Chief of Surgery at Harper University Hospital, Chairman of Department of Surgery & Professor of Surgery at Wayne State University School of Medicine

Office address: Harper Pro, Suite 400, 540 E. Canfield, Detroit, MI 48201

Phone: 1-313-745-4195 (Office), 1-313-745-1873 (Fax)

Email: dweaver@med.wayne.edu 

Specialties & Clinical Interests: Colon cancer, gastrointestinal cancer, endoscopy, lithotripsy, reflux surgery, biliary tract surgery, gall bladder surgery, gastrointestinal surgery, general surgery, laparoscopic hernia surgery, pancreatic surgery.

Research Interest: Pancreatic surgery, Sphincter Sparing Rectal Surgery

Board Certification: Surgery

Education

M.D.: Loma Linda University School of Medicine

Residency & Fellowship: General Surgery, Wayne State University, Detroit, MI

_________________________________________________________________________________

Oksana V Gruzdyn, B.S.

Title: Research Assistant

Michael & Marian Ilitch Department of Surgery 

Wayne State University School of Medicine (WSUSOM)

4201 St. Antoine Avenue, Detroit, MI 48201

Office Address: Scott Hall, Room # 6228, 540 E Canfield St, WSUSOM, Detroit, MI 48201. 

Office Telephone: (313) 577-5315

Email: ovgruzdy@med.wayne.edu

Specialty: Pancreatic, Ovarian cancers and Multiple Myeloma

Clinical Interest: Immunotherapy

Research Interest: Chimeric Antigen Receptor (CAR) T cell therapy, COVID-19 vaccines

Education

B.S., Wayne State University, Detroit, MI

_________________________________________________________________________________ 

Katia Hermes, B.S.

Title: Research Assistant

Michael & Marian Ilitch Department of Surgery 

Wayne State University School of Medicine (WSUSOM)

4201 St. Antoine Avenue, Detroit, MI 48201

Office Address: Scott Hall, Room # 6228, 540 E Canfield St, WSUSOM, Detroit, MI48201. 

Office Telephone: (313) 577-5315

Email: katia.hermes@wayne.edu

Specialty: SARS-CoV-2 vaccine

Clinical Interest: Cancer biology, and immunotherapy

Research Interest: Chimeric Antigen Receptor (CAR) T cell therapy, and COVID-19 vaccines

Education

B.S., Wayne State University, Detroit, MI

_________________________________________________________________________________ 

Sahil Bawa, MBBS, MD

Title: Research Scholar (Clinical)

Michael & Marian Ilitch Department of Surgery 

Wayne State University School of Medicine (WSUSOM)

4201 St. Antoine Avenue, Detroit, MI 48201

Office Address: Scott Hall, Room # 6228, 540 E Canfield St, WSUSOM, Detroit, MI48201. 

Office Telephone: (313) 577-5315.

Specialty: Renal cell Carcinoma.

Clinical Interest: Immunotherapy.

Research Interest: Chimeric Antigen Receptor (CAR) T cell therapy,

Therapeutic vaccine for Renal Cell Carcinoma, COVID-19 Vaccine.

Education: MBBS, MD, Punjab, India

_________________________________________________________________________________

Bala Krishna Kolli, M.Phil., Ph.D.

Title: Adjunct Assistant Professor

Michael & Marian Ilitch Department of Surgery 

Wayne State University School of Medicine (WSUSOM)

4201 St. Antoine Avenue, Detroit, MI 48201

Office Address: Scott Hall, Room # 6228, 540 E Canfield St, WSUSOM, Detroit, MI 48201. 

Office Telephone: (313) 577-5315.

Email: bkolli@wayne.edu 

Specialty: Pancreatic, Ovarian, colorectal cancers and Multiple Myeloma

Clinical Interest: Immunotherapy

Research Interest: Chimeric Antigen Receptor (CAR) T cell therapy, cancer immunotherapy with recombinant antibodies (biologicals), COVID-19 vaccines

Education

M.Sc. (Ag), Banaras Hindu University, Varanasi, India

M.Phil., Ph.D., Jawaharlal Nehru University, New Delhi, India.

Post-doctoral/Research Associate: Jacob Blaustein Institute for Desert Research, Sde Boqer, Israel/Jawaharlal Nehru University, New Delhi. India/Rosalind Franklin University of Medicine and Science, North Chicago, IL.

PUBLICATIONS:

PEER REVIEWED PUBLICATIONS (2010-2013)

Batchu RB, Gruzdyn O, Weaver DW, Gruber SA. MAGE-A3 With Cell-Penetrating Domain as an Efficient Therapeutic Cancer Vaccine. JAMA surgery 03/2014; DOI:10.1001/jamasurg.2013.4113.

Ramesh B. Batchu, Oksana V Gruzdyn, Christopher S Bryant, Aamer M Qazi, Sanjeev Kumar, Sreedhar Chamala, Shu T Kung, Ramana S Sanka, Udaya S Puttagunta, Donald W Weaver, Scott Gruber. Ritonavir-Mediated Induction of Apoptosis Occurs via RB/E2F-1 and AKT Pathways in Pancreatic Cancer. Pharmaceuticals 2014, 7, 46-57.

Ramesh B. Batchu, Oksana V Gruzdyn, Shu T Kung, Donald W Weaver, Scott Gruber. Dendritic cell based immunotherapy of cancer with cell penetrating domains.. Indian J Surg Oncol. 2014, 5, 3-4.

Ramesh B. Batchu, Oksana Gruzdyn, Shu T. Kung, Scott A. Gruber. Dendritic cell based immunotherapy of cancer with cell penetrating domains. Indian J Surg Oncol, DOI 10.1007/s13193-013-0277-01.2013, 2014

Batchu RB, Gruzdyn OV, Moreno-bost AM, et al. Efficient lysis of epithelial ovarian cancer cells by MAGE-A3-induced cytotoxic T lymphocytes using rAAV-6 capsid mutant vector. Vaccine. 2014 Jan 6. pii: S0264-410X(13)01792-1. doi: 10.1016/j.vaccine.2013.12.049.

RB Batchu PhD, AM Qazi PhD, OV Gruzdyn BS, A Semaan MD, S Seward MD, S Chamala MD, VB Dhulipala MD, DL Bouwman MD, DW Weaver MD, & SA Gruber MD, PhD, MBA. EZH2-shRNA Mediated Up-regulation of p21waf1/cip1 and its Transcriptional Enhancers with Concomitant Down-modulation of Mutant p53 in Pancreatic Ductal Adenocarcinoma. 2013. Surgery, In Press.

Seward S, Semaan A, Qazi AM, Gruzdyn OV, Chamala S, Bryant CC, Kumar S, Cameron D, Sethi S, Ali-Fehmi R, Morris R, Bouwman DL, Munkarah AR, Weaver DW, Gruber SA, Batchu RB. EZH2 blockade by RNA interference inhibits growth of ovarian cancer by facilitating re-expression of p21waf1/cip1 and by inhibiting mutant p53. Cancer Lett. 336: 53-60. PMID: 23603558. 2013.

Aamer M Qazi, Oksana Gruzdyn, Assaad Semaan, Shelly Seward, Sreedhar Chamala, Vasu Dhulipala, Seema Sethi, Rouba Ali‐Fehmi, Philip A Philip, David L Bouwman, Donald W Weaver, Scott A Gruber, Ramesh B Batchu. Restoration of E-Cadherin expression in pancreatic ductal adenocarcinoma treated with microRNA-101. Surgery 152: 704-11. PMID: 22943841. 2012.

Mahdi, Haider; Kumar, Sanjeev; Seward, Shelly; Semaan, Assaad; Batchu, Ramesh; Lockhart, David; Tamimi, Hisham; Munkarah, Adnan R. Prognostic Impact of Laterality in Malignant Ovarian Germ Cell Tumors. Int J Gynecol Cancer, 21: 257-262. PMID: 21475076. 2011.

Pal J, Bertheau R, Buon L, Qazi A, Batchu RB, Bandopadhyay S, Ali-Fehmi R, Beer DG, Weaver DW, Reis RS, Goyal RK, Huang Q, Munshi NC, Shammas MA. Genomic evolution in Barrett’s adenocarcinoma cells: critical roles of elevated hsRAD51, homologous recombination and Alu sequences in the genome. Oncogene, 30: 3585-98. PMID: 21423218. 2011.

Assaad Semaan, Aamer M. Qazi, Shelly Seward, Sreedhar Chamala, Vasu B. Dhulipala, Seema Sethi, Rouba Ali-Fehmi, Robert Morris, Christopher P. Steffes, David L. Bouwman, Adnan R Munkarah, Donald W. Weaver, Scott A. Gruber & Ramesh B. Batchu. miR-101 inhibits growth of ovarian cancer xenografts by relieving chromatin-mediated transcriptional repression of p21waf1/cip1.Pharmaceutical Res, 28: 3079-90. PMID: 21818714. 2011.

Christopher S. Bryant, M.D., Sanjeev Kumar, M.D., Aamer Qazi, Ph.D., Robert T. Morris, M.D., Christopher P Steffes, M.D., Madhu Prasad, M.D., Donald Weaver, M.D., Masood Shammas, Ph.D., & Ramesh B. Batchu, Ph.D. Sulforaphane Induces Cell Cycle Arrest by Protecting RB-E2F-1 Complex in Epithelial Ovarian Cancer Cells. Mol Cancer, 9:47. PMID: 20196847. 2010.

Bryant CS, Munkarah AR, Kumar S, Batchu RB, Shah JP, Morris RT, Jiang ZL Saed GM. Reduction of hypoxia-induced angiogenesis in ovarian cancer cells by inhibition of HIF-1alpha gene expression. Arch Gynecol Obstet, 282:677-83. PMID: 20140681. 2010.

Qazi A, Pal J, Maitah M, Fulciniti M, Pelluru D, Nanjappa P, Lee S, Batchu RB, Prasad M, Bryant CS, Rajput S, Gryaznov S, Beer DG, Weaver DW, Munshi NC, Goyal RK, Shammas MA. Anticancer activity of a broccoli derivative, sulforaphane, in barrett adenocarcinoma: potential use in chemoprevention and as adjuvant in chemotherapy. Transl Oncol. 3: 389-99. PMID: 21151478. 2010.

BOOK AUTHORSHIPS, EDITORSHIPS, AND CHAPTERS

Laser capture microdissection of pancreatic ductal adeno-carcinoma cells to analyze EzH2 by Western Blot analysis. Aamer M Qazi; Sita Aggarwal; Christopher S Steffer; David L Bouwman; Donald W Weaver; Scott A Gruber; Ramesh B Batchu. Methods Mol Biol, 755:245-56. PMID: 21761309. 2011.

Crippling of HIV at Multiple Stages with Recombinant Adeno-Associated Viral Mediated RNA Interference. Oksana V. Gruzdyn, Aamer M. Qazi1, Assaad Y. Semaan, Shelly M. Seward, Christopher P. Steffes, David L. Bouwman, Donald W. Weaver and Scott A. Gruber. Recent Translational Research in HIV/AIDS. Edited by Prof. Yi-Wei Tang.. Publisher InTech. ISBN 978-953-307-719-2. 2011.

Genomic Medicine Today. David Ellis and Ramesh Babu Batchu. Hospital & Health Networks Daily RSSj. October, 2011.

NON PEER REVIEWED PUBLICATIONS (2009-2013)

Impact of Sulforaphane, alone or in combination with paclitaxel, on cell growth, genome-wide expression profile, and genomic integrity in Barrett’s adeno-carcinoma cells. A. Qazi, K. B. Stark, R. B. Batchu, S. Chamala, C. S. Bryant, C. P. Steffes, D. G. Beer, D. W. Weaver, M. Prasad, M. A. Shammas. J Surg Res, 151: 252, 2009

Impact of Sulforaphane, Alone or in Combination with Paclitaxel, on Cell Growth, Genome-Wide Expression Profile, and Genomic Integrity, in Barrett’s Adenocarcinoma Cells. A. Qazi, K.B. Stark, R.B. Batchu, S. Chamala, C.S. Bryant, C.P. Steffes, D.G. Beer, D.W. Weaver, M. Prasad, M.A. Shammas. J Surg Res, Vol. 151, Issue 2, Page 252, 2009

Expression of Mir-101 Inhibits Cell Growth and Proliferation by Down Regulation of EZH2 in PANC-1 Cells Both In Vitro and In Vivo. Ramesh B. Batchu, Aamer Qazi, Assaad Semaan, Sreedhar Chamala, Shelly Seward, Christopher P. Steffes, Masood A. Shammas, Donald W. Weaver. Gastroenterology. Volume 138, Issue 5, Supplement 1, Pages S-548-S-549, 2010

EZH2 Knock Down by Lentiviral shRNA Inhibits Pancreatic Ductal Adeno-Carcinoma Cell Proliferation In Vitro and Tumor Growth In Vivo. Ramesh B. Batchu, Aamer Qazi, Shelly Seward, Masood A. Shammas, Sreedhar Chamala, Assaad Semaan, Christopher P. Steffes, Donald W. Weaver.  Gastroenterology. Volume 138, Issue 5, Supplement 1, Pages S-548, 2010

Anticancer Activity of a Broccoli Derivative, Sulforaphane, in Barrett’s Adenocarcinoma: Potential use in Chemoprevention and as Adjuvant in Chemotherapy. Aamer Qazi, Jagannath Pal, Ma’in Maitah, Mariateresa Fulciniti, Dheeraj Pelluru, Puru Nanjappa, Ramesh B. Batchu, Madhu Prasad, Christopher S. Bryant, Samiyah Rajput, Saem Lee, Kenneth C. Anderson, Sergei Gryaznov, David G. Beer, Donald W. Weaver, Nikhil C. Munshi, Raj K. Goyal, Masood A. Shammas. Gastroenterology Vol. 138, Issue 5, Supplement 1, Page S-500. 2010

Role of Recombinase (RAD51) in Ongoing Genomic Instability and Proliferation in Barrett’s Adenocarcinoma Cells. Jagannath Pal, Robert C. Bertheau, Leutz Buon, Aamer Qazi, Ramesh B. Batchu, Rouba Ali-Fehmi, Saem Lee, David G. Beer, Donald W. Weaver, Nikhil C. Munshi, Raj K. Goyal, Masood A. Shammas. Gastroenterology Vol. 138, Issue 5, Supplement 1, Page S-505. 2010

PI 3-Kinase Inhibitor (Wortmannin) Inhibits DNA Recombination, Genomic Instability, and Growth of Barrett’s Adenocarcinoma Cells. Jagannath Pal, Mariateresa Fulciniti, Leutz Buon, Aamer Qazi, Samir B. Amin, Ramesh B. Batchu, Saem Lee, David G. Beer, Kenneth C. Anderson, Donald W. Weaver, Nikhil C. Munshi, Raj K. Goyal, Masood A. Shammas. Gastroenterology Vol. 138, Issue 5, Supplement 1, Pages S-499-S-500, 2010

Relationship of miR-101 and targeted epigenetic silencing of EzH2 on cell growth and invasiveness in ovarian cancer cells. R. B. Batchu, A. Semaan, S. M. Seward, A. Qazi, S. Chamala, C. S. Bryant, C. Steffes, S. Kumar, M. A. Shammas, D. W. Weaver. J Clin Oncol 28 (suppl; abstr e15538) 2010

B Cell Transduction of Capsid Mutant (Y730F) Adeno-Associated Virus-2 Vectors with Mage-A3 Gene for Immunotherapy of Colorectal Cancer. R.B. Batchu, A.M. Qazi, S. Seward, M. Haider, K. Khalil, A. Semaan, C. Steffes, P. Madhu, D.W. Weaver.  J Surg Res, Vol. 158, Issue 2, Page 197, 2010

Epigenetic Silencing of EzH2 By RNA Interference As A Potential Therapy For Pancreatic Adenocarcinoma. R.B. Batchu, A.M. Qazi, A.Y. Semaan, S.M. Seward, S. Chamala, V.B. Dhulipala, C. David, C.S. Bryant, S. Kumar, C. Steffes, P. Philip, D. Bouwman, D.W. Weaver.  J Surg Res, Vol. 165, Issue 2, Page 178, 2011
MicroRNA-101 (miR-101) Enhances Chemosensitivity of Pancreatic Ductal Adenocarcinoma (PDAC) Cells By Inhibition of MTOR Signaling Via PRAS40. R.B. Batchu, O. Gruzdyn, A.M. Qazi, D. Bouwman, S.A. Gruber, D.W. Weaver. J Surg Res, Vol. 172, Issue 2, Page 233, 2012

MicroRNA-101 (miR-101) Promotes Expression of E-cadherin (E-Cad) By Relieving Epigenetic Repression in Epithelial Ovarian Cancer (EOC). R.B. Batchu, O. Gruzdyn, A.M. Qazi, A. Semaan, D. Bouwman, D.W. Weaver, S.A. Gruber. J Surg Res, Vol. 172, Issue 2, Pages 313-314, 2012

Negative Regulation of Mutant P53 by MicroRNA-101 (miR-101) in Pancreatic Ductal Adenocarcinoma (PDAC). R.B. Batchu, O. Gruzdyn, A. Qazi, S.T. Kung, D.W. Weaver and S.A. Gruber. Journal of Surg Res, Vol. 179, Issue 2 , Page 341, 2013

INVITED LECTURES (2012-2013)

Enhancer of Zeste Homolog 2 (EZH2) Silencing Down-modulates Mutant p53 with Increased Chemosensitivity in Epithelial Ovarian Cancer (EOC). Ramesh B. Batchu PhD, Oksana Gruzdyn BS, Aamer M. Qazi PhD, Shelly Seward MD, Donald W. Weaver, MD, Scott A. Gruber, MD, PhD, MBA. American College of Surgeons (ACS) Clinical Congress, Washington, DC, October 7th, 2013.

Enhanced dendritic cell permeability of genetically engineered MAGE-A3 with cell penetrating domain (CPD) for the generation of an efficient therapeutic cancer vaccine. Batchu RB, Gruzdyn O, Kung ST, BS, Weaver D, Gruber SA. Association of VA Surgeons (AVAS), Milwaukee, WI , April, 21-23, 2013.

EZH2-shRNA mediated up-regulation of p21WAF1/CIP1 and its transcriptional enhancers with concomitant down-modulation of mutant p53 in pancreatic ductal adeno-carcinoma (PDAC). RB Batchu, OV Gruzdyn, AM Qazi, DW Weaver, SA Gruber. Central Surgical Association (CSA) Omni Amelia Island Plantation – Amelia Island, FL, March 14-16, 2013.|

Negative Regulation Of Mutant P53 By MicroRNA-101 (miR-101) In Pancreatic Ductal Adenocarcinoma (PDAC). R. B. Batchu, O. Gruzdyn, A. Qazi, S.T. King, D.W. Weaver, S.A. Gruber. ASC20130348. 8th Annual Academic Surgical Congress (ASC), New Orleans, LA, February 5-7, 2013.

R. B. Batchu, Inhibition of mammalian target of rapamycin (MTOR) signaling by microrna-101 (mir-101) results in enhanced chemosensitivity of epithelial ovarian cancer (EOC) cells. Association of VA surgeons, 36th Annual Meeting, April 1-3, 2012.

R. B. Batchu, Restoration Of E-Cadherin (E-Cad) Expression In Pancreatic Ductal Adenocarcinoma (PDAC) Treated With MicroRNA-101 (MiR-101). Central Surgical Association, Annual Meeting. March 1-3, Madison, Wisconsin, 2012.

Ramesh B. Batchu, Oksana Gruzdyn, Donald. W. Weaver and Scott A. Gruber. Novel Tyrosine Mutant Recombinant Adeno-associated Viral (rAAV) Transduction of Dendritic Cells (DCs) as a Step Towards Therapeutic Vaccination in Multiple Myeloma (MM) ACS 98th Annual Clinical Congress, Sep 30 – Oct 4, Chicago, IL, 2012.

R. B. Batchu, MicroRNA-101 (miR-101) Enhances Chemosensitivity Of Pancreatic Ductal Adenocarcinoma (PDAC) Cells By Inhibition Of MTOR Signaling Via PRAS40. 7th Annual Academic Surgical Congress – February 14-16, Las Vegas, Nevada, 2012.

R. B. Batchu, MicroRNA-101 (miR-101) Promotes Expression Of E-cadherin (E-Cad) By Relieving Epigenetic Repression In Epithelial Ovarian Cancer (EOC), 7th Annual Academic Surgical Congress – February 14-16, Las Vegas, Nevada, 2012.

R. B. Batchu, A. M. Qazi, A. Y. Semaan, S. M. Seward, S. Chamala, V. B. Dhulipala, C. David, C. S. Bryant, S. Kumar, C. Steffes, P. Philip, D. Bouwman, D. W. Weaver. “Epigenetic Silencing Of EzH2 By RNA Interference As A Potential Therapy For Pancreatic Adenocarcinoma” Sixth Annual Academic Surgical Congress, Session; Oncology – Oncology Basic Science: Cell Signaling & Apoptosis. Huntington Beach, CA, Feb 01, 2011.

R. B. Batchu, A. M. Qazi, S. Seward, M. Haider, K. Khalil, A. Semaan, C. Steffes, P. Madhu, D. W. Weaver. B Cell Transduction Of Capsid Mutant (Y730F) Adeno-Associated Virus-2 Vectors With Mage-A3 Gene For Immunotherapy Of Colorectal Cancer. Session: Oncology 3: Targeted Therapy/Immunobiology and Therapy. 5th Annual Academic Surgical Congress. San Antonio, TX. February 3,2010.

R. B. Batchu, A. Qazi, K. B. Stark, S. Chamala, C. S. Bryant, C. P. Steffes, D. G. Beer, D. W. Weaver, M. Prasad, M. A. Shammas; Impact Of Sulforaphane, Alone Or In Combination With Paclitaxel, On Cell Growth, Genome-Wide Expression Profile, And Genomic Integrity, In Barrett’s Adenocarcinoma Cells. 4th Annual Academic Surgical Congress. Session: Oncology 5, apoptosis. Fort Myers, FL, February 3-6, 2009.

Ramesh B. Batchu, “Ritonavir mediated protection of retinoblastoma-E2F-1 complex at G1 phase of cell cycle in pancreatic cancer cell lines” ACS 94th Annual Clinical Congress: (SF23) Surgical Oncology, San Francisco, CA, October 12-16, 2008.