Christopher James Bakkenist, PhD

  • Associate Professor of Radiation Oncology
  • Julius Paul and Freeda Greenberger Chair in Radiation Oncology Research
  • Vice Chair for Basic Science

I lead a research laboratory in the Hillman Cancer Center that determines the therapeutic potential of novel pharmacologic agents in preclinical models of lung and head and neck cancers. We work with the Lung and Head and Neck SPOREs as well as AstraZeneca to move innovative medicines to Phase 1 and Phase 2 clinical trials. Through training outstanding medical and graduate students, residents, and postdoctoral fellows, we will identify new strategies to improve outcomes in radiation oncology.

Teaching Activities

Rational Use of Drugs Workshop - Conference (2 hrs)
Department of Pharmacology & Chemical Biology
University of Pittsburgh School of Medicine

Adrenergic Pharmacology Workshop - Conference (2 hrs)
Department of Pharmacology & Chemical Biology
University of Pittsburgh School of Medicine

Cholinergic Pharmacology Workshop - Conference (2 hrs)
Department of Pharmacology & Chemical Biology
University of Pittsburgh School of Medicine

Cancer Biology and Therapeutics

Course Number: MSCMP 3710 MSPHL 3310
DNA damage signaling and DNA repair signaling
Department of Pharmacology & Chemical Biology
University of Pittsburgh School of Medicine

Protein Sorting-Physiology and Pathophysiology (2 hrs)
Department of Pharmacology & Chemical Biology
University of Pittsburgh School of Medicine

Breast Cancer Pharmacology and Pathology (2 hrs)
Department of Pharmacology & Chemical Biology
University of Pittsburgh School of Medicine

DNA Repair: Biochemistry to Human Disease
Course Number:
  MSMPHL 3330 and MSBMG 3530
Course Director: Five Lectures
The Integrated Program in Biomedical Sciences and the Departments of Molecular Biology and Genetics & Pharmacology; University of Pittsburgh School of Medicine

MSTP Professional Development III  - Grant Writing & Networking
Course Director: Ten LecturesI direct and teach this ten week course on grant writing for the MSTP students
University of Pittsburgh School of Medicine

MSMPHL 2390 Directed Study 17948 for 2 credits – Grant Writing & Networking
Course Director: Six LecturesI direct and teach this six week course on grant writing for the Molecular Pharmacology Graduate Students
University of Pittsburgh School of Medicine

2 PhD rotations students: Eleanor Johnston and Lisa Beppu

1 PhD student joined the lab: Eleanor Johnston

2 PSTP rotations students: Pooja Karukonda and Aranee Sivananthan

1 PSTP student joined the lab: Pooja Karukonda

Representative Publications

Forero A, Giacobbi NS, McCormick KD, Gjoerup OV, Bakkenist CJ, Pipas JM, Sarkar, SN.  (2014) SV40 Large T antigen induces ISGs through ATR Kinase. The Journal of Immunology, 192, 5933-5942

Teng P-N, Bateman NW, Darcy KM, Hamilton CA, Maxwell GL, Bakkenist CJ, Conrads TP.  (2015)  Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells.  Gynecologic Oncology, 136, 554-561

Bakkenist CJ, Czambel RK, Hershberger P, Tawbi H, Beumer JH, Schmitz JC.  (2015)  A Semiquantitative Dual Multiplexed Immunoblot Method to Simultaneously Analyze ATM and H2AX Phosphorylation in Human Peripheral Blood Mononuclear Cells. Oncoscience, 2, 542-554

Beumer JH, Fu KY, Anyang BN, Siegfried JM, Bakkenist CJ.  (2015)  Functional analyses of ATM, ATR and Fanconi anemia proteins in lung carcinoma.  BMC Cancer, 15, 649

Vendetti FP, Lau A, Schamus S, Conrads TP, O’Connor MJ and Bakkenist CJ.  (2015)  The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient lung cancers in vivo. Oncotarget, Oct 27, 6247

*This Article published the structure of AZD6738 which is in successful Phase 2 trials.

Moiseeva T, Gamper AM, Hood T, Conrads TP, Bakkenist CJ.  (2015)  Human DNA polymerase e is phosphorylated at serine 1940 after DNA damage and interacts with the iron-sulphur complex chaperones CIAO1 and MMS19. DNA Repair, DNA Repair, 43, 9-17

Villaruz L, Jones H, Dacic S, Abberbock S, Kurland BF, Stabile LP, Siegfried JM, Conrad TP, O’Connor MJ, Pierce AJ and Bakkenist CJ. ATM protein is deficient in over 40% of lung adenocarcinomas. Oncotarget, Advance Online Publication

Research Interests

I am a tenured associate professor of Radiation Oncology at the University of Pittsburgh. The long-term goal of my laboratory is to understand how ATM and ATR kinase inhibitors can be used to treat lung cancer. My laboratory is investigating the role of ATM kinase activity in DNA replication and homologous recombination repair. We were the first to show that the cellular consequences of transient ATM kinase inhibition and ATM protein disruption are distinct and that ATM kinase inhibitors poison DNA double-strand break repair complexes. These discoveries are of particular importance in the clinical setting where ATM kinase inhibitors will only be effective for several hours. We showed that ATM binds PCNA in vivo, in the absence of DNA damage, and that this association promotes DNA synthesis by DNA polymerase  in vitro. We are also investigating the cellular consequences of ATR kinase inhibition. We were the first to show that ATR kinase activity is initiated in G1-phase cells after exposure to ionizing radiation. These unexpected data implicate ATM in DNA replication and ATR in G1-phase metabolism.  

More recently we obtained 30 grams of orally active and bioavailable ATM and ATR kinase inhibitors through our collaboration with AstraZeneca and shifted our focus to animal studies. My laboratory’s efforts were critical to the identification of the first orally active ATM kinase inhibitor AZD31, and we are one of only two academic groups worldwide to have this compound. The ATR kinase inhibitor AZD6738 is a clinical compound that has been given to between 5 and 10 patients in Phase I clinical trials at the time of submission. The extensive preliminary data in this proposal documents much of our unpublished animal work. We show that inhibition of DNA damage signaling by ATR kinase during treatment with cisplatin and IR is well-tolerated and leads to durable responses in mouse xenograft and genetic models of lung cancer. Furthermore, we show that ATR kinase inhibitors are more potent radiosensitizers than ATM kinase inhibitors in a mouse model of lung cancer by virtue of lower toxicity. The clear and dramatic response of lung cancer to radiation in combination with ATR kinase inhibitor led us to discover unexpected crosstalk between ATR kinase signaling and immune checkpoints.

I am working with the UPCI SPORE in Lung Cancer as well as AstraZeneca to complete of Phase I trials with ATR kinase inhibitors in lung cancer and the Henry M. Jackson Foundation for the Advancement of Military Medicine to complete Phase I trials with ATR kinase inhibitors in gynecologic cancers. I attend weekly Phase I group meetings and have developed the phosphorylation on ATM serine-1981 as a clinical biomarker both in peripheral blood mononuclear cells and tumor specimens for target for efficacy and target engagement by clinical ATM and ATR kinase inhibitors.

Research Grants

Faculty Support on Research grants is 76 percent

Source/Grant Number: NIH / RO1CA148644

Grant Title: Regulation of DNA replication fork progression by ATM kinase activity

Role in Project & Percentage of Effort: Principal Investigator (6 calendar months)

Years Inclusive: 3/4/11 - 2/29/16

Direct Dollars (total/annual): $830,000 ($166,000 annual)

Indirect Dollars (total/annual): $427,450 ($85,490 annual)

Supplement: $30,000

 

Source/Grant Number: NIH P50CA090440-09 SPORE in Lung Cancer                       

Grant Title: Project 4 - Preclinical Assessment of Bioavailable and Orally Active ATR Kinase Inhibitors for the Treatment of Lung Cancer

Role in Project & Percentage of Effort: Principal Investigator (3 calendar months)

Years Inclusive: 9/1/13 - 8/31/16

Direct Dollars (total/annual): $112,025

Indirect Dollars (total/annual): $57,692

 

Source/Grant Number: AstraZeneca

Grant Title: AZD6738/ATRi and AZD0156/ATMi as radiosensitizers: 223Ra (Xofigo) combinations

Role in Project & Percentage of Effort: Principal Investigator (0 calendar months)

Years Inclusive: 7/1/15 - 6/30/16

Direct Dollars (total/annual): $75,774

Indirect Dollars (total/annual): $44,707

 

Source/Grant Number: UPP

Grant Title: ATR kinase inhibitors for the treatment of lung cancer

Role in Project & Percentage of Effort: Principal Investigator

Years Inclusive: 2015-2016

Direct Dollars (total/annual): $50,000

Indirect Dollars (total/annual): N/A

 

Source/Grant Number: UPMC Cancer Centers (Stanley Marks, MD)

Grant Title: ATM for the Pharmacodynamic Determination of 223Radium Dichloride in Metastatic Bone Disease

Role in Project & Percentage of Effort: Principal Investigator

Years Inclusive: 2015-2016

Direct Dollars (total/annual): $160,000

Indirect Dollars (total/annual): N/A

 

Source/Grant Number: NIH / NCI / RO1A0 CA166198

Grant Title: Mechanisms of RET/PTC Rearrangement in Thyroid Cancer (Yuri Nikiforov PI)

Role in Project & Percentage of Effort: Co-Investigator (0.5 calendar months)

Years Inclusive: 8/1/13 – 7/31/18

Direct Dollars (total/annual): $1,250,000 ($250,000 annual)

Indirect Dollars (total/annual): $515,000 ($103,000 annual)

 

Source/Grant Number: NIH NCI 1 UM1  CA186690 01  NCI 

Grant Title: ET-CTN WITH PHASE I EMPHASIS AT UPCI

Role in Project & Percentage of Effort: Co-Investigator (0.3 calendar months)

Years Inclusive: 3/25/14-2/28/19

Direct Dollars (total/annual): $561,514

Indirect Dollars (total/annual): $289,179