David Shackelford
University of California-Los Angeles, CA·Medicine & Clinical Research
Many lung tumors stop responding to drugs, even when the drugs first work. Non-small cell lung cancer (NSCLC) was expected to kill about 130,000 people in the US in 2021, and most patients eventually develop resistance to targeted drugs or immunotherapy.
- Fields
Medicine & Clinical Research
Biochemistry
Biomedical Engineering
- Topics
non-small cell lung cancer
lung adenocarcinoma
mitochondria
- Grants
- 2 known grants, through May 2028
What they work on
- Dissect mitochondrial energy production in therapy-resistant lung adenocarcinomas in living models, using 18F-BnTP PET imaging, a scan that reads out mitochondrial membrane potential.
- Analyze the structure and function of adaptive oxygen-based metabolism (OXPHOS) in therapy-resistant KRAS/LKB1 and EGFR mutant lung tumors, to guide treatment with OXPHOS inhibitors.
- Profile oxidative metabolism over time in patients with advanced lung adenocarcinoma using repeated 18F-BnTP PET scans.
- Investigate whether the mTORC1–Drp1 pathway drives mitochondrial splitting and cristae remodeling after LKB1 loss, using 3D scanning blockface electron microscopy in mouse lung tumors.
- Test whether the LKB1/AMPK pathway regulates fat-droplet-associated mitochondria and fatty acid oxidation, and whether PTPMT1 inhibitors make LKB1 mutant tumors respond to chemotherapy again.
More about the research
Shackelford's grants pursue a different idea: sort tumors by how they make energy, not only by their mutations, and then attack that energy source. Both projects focus on mitochondria, the cell's power plants, in lung adenocarcinoma (LUAD), the most common type of NSCLC. They rely on 18F-BnTP, a tracer for positron emission tomography (PET) scans that the lab has shown reports mitochondrial activity in living lung tumors.
Why it matters
Patients with lung cancer whose tumors carry KRAS/LKB1 or EGFR mutations often stop responding to targeted drugs and immunotherapy. A PET scan with the tracer 18F-BnTP could identify which tumors depend on mitochondrial energy. Doctors could then match these patients with drugs that block mitochondria, such as complex I inhibitors. PTPMT1 inhibitors may also help resistant tumors respond to chemotherapy again.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Kwok Kin Wong
New York University, NY·Medicine & Clinical Research
Determine how co-mutations such as MYC, KMT2D, STK11 and PTEN change SCLC plasticity (cells' ability to switch identity) and transcriptional subtypes, using new mouse models built on TP53/RB1-mutant SCLC.
David Tweardy
University of Texas MD Anderson Cancer Center, TX·Medicine & Clinical Research
Determine whether the STAT3 inhibitor TTI-101, alone or combined with anti-PD-1 antibody, treats lung tumors effectively in the K-ras mutant CC-LR mouse model of non-small cell lung cancer.
Nicholas C. Denko
Ohio State University, OH·Medicine & Clinical Research
Determine whether oncogenic NRF2 activation, which can follow KEAP1 mutations, makes lung cancer cells and model tumors dependent on mitochondria and more hypoxic, and whether papaverine or its derivatives sensitize these therapy-resistant tumors.
The school
University of California-Los Angeles: 84 labs on PI Pages, $1.9B a year on research, 803 research doctorates a year.
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