Project 2: Therapeutic Combination of CLR1404 with External Beam Radiation in Head and Neck Cancer

Summary:

Radiation therapy for Head and Neck Cancer (HNC) is commonly associated with normal tissue toxicities, including dry mouth, difficulty swallowing and reduced quality of life (QOL). This research will develop a new technique to reduce the dose of external beam radiation by incorporating a radio-labeled molecule, CLR1404, that delivers tumor-selective internal radiation. This approach holds promise to enhance outcome for HNC patients and improve long term QOL.

 

Specific Aims:

  • AIM 1: Examine uptake and retention of CLR1404 across a diverse panel of HNC xenografts.
  • AIM 2: Quantify the ability of CLR1404 to augment external beam radiation response in HNC model systems.
  • AIM 3: Perform a phase I clinical trial that combines CLR1404 with reduced-dose external beam radiation in patients with loco-regional recurrence following prior HNC radiation.  

Project 2 Team:

Project 2 team
Right to left, Ashley Weichmann, BA, Kwang Nickel, PhD, Reinier Hernandez, PhD, Joe Grudzinski, PhD, Jamey Weichert, PhD, Henry Feldman, Paul Harari, MD, Ian Marsh, BS, Bryan Bednarz, PhD, Mahyar Abbariki, Shari Piaskowski, BS, Jenna Mylin, Lindsey Abel, MS, Roxana Alexandridis, PhD, Chunrong Li, PhD

Collaborators:

Jamey Weichert, PhD

Jamey Weichert, PhD

Professor
Radiology
University of Wisconsin

 

Bryan Bednarz, PhD
Bryan Bednarz, PhD

Associate Professor
Medical Physics
University of Wisconsin

 

Albert Van der Kogel, PhD
Albert Van der Kogel, PhD

Professor
Human Oncology
University of Wisconsin

Learn more:

Approximately 50 percent of patients with head and neck cancer (HNC) manifest recurrence following initial treatment, and the majority of these recurrences are loco-regional (mouth, throat, neck). Although a proportion of these patients remain potentially curable with further local treatment approaches (surgery, radiation, chemoradiation), retreatment is technically challenging and accompanied by a significant risk of irreversible damage to normal tissues. Surgery is often limited by tumor adherence to critical structures (base of skull, neurovascular bundles), whereas radiation is often limited by normal tissue tolerance (spinal cord, bone, cartilage). Although often warranted in the attempt to provide disease control, HNC retreatment can induce profound adverse effects on patient health-related quality of life (QOL). There is a compelling need to identify improved treatment approaches for patients with loco-regional HNC recurrence.

In this project, we test a highly promising new radiolabeled molecule (CLR1404) developed over the last decade at the University of Wisconsin. CLR1404 provides the opportunity for tumor-selective internal delivery of radiation, thereby enabling combination with reduced dose external beam radiation in the treatment of HNC. This agent shows selective accumulation and retention in human tumors across a broad spectrum of animal models (more than 50 xenograft models to date, including our HNC patient-derived xenografts) and in our first human HNC patients tested. CLR1404 is a radiolabeled phospholipid ether analog with powerful potential as an imaging agent (labeled with 124I) and as a therapy agent (labeled with 131I). This “diapeutic approach” (diagnostic and therapeutic) exploits the unique capabilities of this molecule. CLR1404 is an alkyl phosphocholine, the lead compound emerging from more than 15 years of laboratory investigation. Approximately 30 radio-iodinated analogs were designed, synthesized and evaluated to select CLR1404 based on various features, including tumor specific uptake, retention and pharmacokinetic profile. Plasma membrane lipid rafts serve as the portal of entry for CLR1404, and the greater abundance of lipid rafts in cancer cells vs. normal cells provides therapeutic selectivity for this approach. CLR1404 has the ability to specifically target tumors while limiting dose to surrounding normal tissuesa scenario very difficult to achieve in HNC even with the use of highly conformal radiation techniques.

The selective tumor accumulation and retention of CLR1404 affords the opportunity to investigate both cancer imaging and therapy applications. A phase I dosimetry study (eight patients, non-HNC) has been completed and published, demonstrating selective tumor uptake and retention of CLR1404 and confirming an excellent drug safety profile. More than 60 cancer patients have now been accrued to four imaging/safety trials and one phase I therapy trial at the University of Wisconsin with CLR1404. We have enrolled three HNC patients to one of the dedicated imaging trials confirming excellent tumor uptake and retention of CLR1404. In this project, we will investigate the therapeutic value of CLR1404 in HNC xenograft models, validate the Monte Carlo dosimetry platform for modeling CLR1404 radiation dose in human tumors and normal tissues and conduct the first phase I clinical trial dedicated to HNC patients. We hypothesize that CLR1404 will induce a tumor response in HNC model systems and demonstrate a favorable tolerance and response profile in a phase I clinical trial for recurrent HNC patients in combination with external beam radiation. Strong emphasis will be placed on patient QOL evaluation as a critical issue for patients with recurrent HNC.

  • AIM 1:  Examine uptake and retention of CLR1404 across a diverse panel of HNC xenografts. Studies will include our recently established HPV-positive and HPV-negative patient-derived xenografts (PDX) to explore CLR1404 uptake and biomarker correlation in this unique HNC resource.
  • AIM 2: Quantify the ability of CLR1404 to augment external beam radiation response in HNC model systems. Single and fractionated radiation experiments will be performed to examine CLR1404 as a modifier of external beam radiation.
  • AIM 3: Perform a phase I clinical trial that combines CLR1404 with reduced-dose external beam radiation in patients with loco-regional recurrence following prior HNC radiation. This trial will examine feasibility, toxicity, tumor response and patient QOL and highlight the use of CLR1404 PET imaging as an ideal biomarker to guide subsequent therapy with CLR1404 (diapeutic approach).