Disease-focused Drug Discovery and Development in Pancreas Cancer

Image

Current personnel, from left to right: Dandan Li, Biologist, Sitanshu Singh, Postdoctoral Fellow (Visiting), Soumita De, Postdoctoral Fellow (Visiting), Udo Rudloff, Head Translational Oncology Section POB, Saifun Nahar, Postdoctoral Fellow (Visiting), Rushikesh Sable, Research Fellow, Anju Kumari, Postdoctoral Fellow (Visiting)

Our laboratory aims to address the unmet medical need for more effective treatments of pancreas cancer patients. The overarching goal of the program is the development of novel therapeutics and therapeutic strategies to improve the life of pancreas cancer patients. Discoveries in the laboratory are tested in focused safety and proof-of-concept clinical trials, and observations made in the clinic are fed back to the laboratory to generate improved hypotheses and refine further preclinical research. Preclinical studies currently range from early structure-activity, in vitro, cell-based and in vivo evaluations, to PK, toxicokinetic, and IND enabling studies. Clinical protocols currently include the first-in-human protocol of metarrestin (ML-246) as a novel treatment for cancer metastasis. Many of these research efforts are conducted within a network of close collaborations which include medicinal chemists, biologists, pharmacologists, toxicologists, and regulatory experts from NCI, NCATS, Kansas University, and small pharma, whose expertise and contributions support further productive drug discovery and clinical translation.

I. Precision targeting of CD206^high tumor associated macrophages

Rationale for tumor associated macrophages (TAMs) as a drug target

Cancer immunotherapy approaches in the form of immune checkpoint inhibitor or chimeric antigen receptor (CAR) T cell therapy have become first- or second-line treatment options in certain cancers, and in some patients confer sustained, durable treatment responses generally not observed with standard systemic chemotherapy. To-date, these positive findings are limited to immunologically ‘hot’ cancers. To the contrary, in the greater majority of solid organ cancers including pancreas cancer, which are classified as immunologically ‘cold’, the promise of immunotherapy via T cell activation has so far proven to be largely evasive. These tumors create an immune milieu which excludes cytotoxic T cells and/or induces ‘exhausted’ T cell phenotypes through an abundance of immune evasive cues frequently involving myeloid immune cells. Strategies that reinvigorate myeloid immune cells and convert cold tumors into immunologically hot, T cell-inflamed phenotypes would be a major advance in the field. Tumor associated macrophages frequently represent the largest fraction of myeloid cell infiltration in the tumor microenvironment (TME) of solid cancers. In the TME, TAMs exhibit a continuum of macrophage subsets with different functionalities and phenotypes ranging from ‘M1-like’ populations with proinflammatory, anti-tumor features to the CD163- and CD206-positive ‘M2-like’ immune suppressive, pro-tumor macrophage populations predominant in evolved cancers.

The mannose receptor 1 (Mrc1; CD206) is a bona fide innate immune checkpoint and immunotherapy drug target in oncology

Previous work by our group has identified the mannose receptor 1 (CD206) expressed on tumor associated macrophages (TAMs) as a novel stimulatory immune checkpoint and immuno-oncology target across different solid organ cancers. Activation of the CD206 receptor on CD206^high TAMs reprograms and retools these cells hijacked by immune evasive cancer cells to mount effective innate and adaptive anti-tumor responses, sensitizes immune checkpoint inhibitor (ICI)-unresponsive tumors to PD-1/PD-L1 inhibition, and cooperates with standard-of-care therapies to improve tumor control.

A focus on small molecule drug development

The identification of CD206 as a novel innate immune checkpoint galvanized the development of a multidisciplinary, diverse drug development and translational research program by my group which has generated a comprehensive portfolio of small molecule-, therapeutic peptide, and nanobody-based CD206-targeting candidates with the goals of clinical translation and commercialization of the most promising candidate(s). In contrast to current primarily monoclonal antibody (mAb)-based immune checkpoint inhibitor (ICI) therapies, our program focuses on the development of small molecules to leverage improved tumor penetration and increased flexibility in difficult to perfuse cancers like pancreas cancer.

II. Preclinical and clinical development of metarrestin

Metarrestin is a novel small molecular inhibitor with selective activity against the metastatic phenotype of cancer cells.  Metarrestin targets a small nuclear structure, the peri-nucleolar compartment (PNC), and has impressive activity in pancreatic cancer metastasis models. Extensive pharmacokinetic studies have shown excellent tissue penetration of the drug with plasma : tumor AUC ratios exceeding 1 : 30 and intratumoral drug levels close to 100µM at non-toxic dose levels. Metarrestin is an oral treatment and is currently tested in a first-in-human clinical trial treating patients with advanced cancers. Metarrestin is well tolerated at dose levels reaching therapeutic levels in tumors. Despite preclinical toxicokinetic studies showing an increased risk of seizures and neurological side effects at high toxic dose levels in dogs, no serious side effects have been observed in patients treated with metarrestin at NIHs Clinical Center and the Kansas University Medical Research Institute. In the absence of dose limiting toxicities, dose escalation continues. Preclinical work conducted in parallel to clinical testing has identified a unique mechanism of action; metarrestin disrupts nucleolar ultrastructure and inhibits rDNA transcription which is informing break clinical biomarker development and future combination treatments.