Enhancing Drug Discovery and Development
The discovery and development of new therapeutic agents for cancer is essential for continued progress against the disease. Historically, NCI has played a vital role in cancer drug discovery and development, and, today, that role continues. Frequently, NCI’s drug development efforts focus on unmet needs that are not being adequately addressed by the private sector.
NCI’s cancer drug discovery and development activities originated from a congressionally mandated initiative known as the Cancer Chemotherapy National Service Center (CCNSC), which, in 1955, established a national resource to facilitate the evaluation of potential anticancer agents. In 1976, the CCNSC’s functions were incorporated into the Developmental Therapeutics Program (DTP) in NCI’s Division of Cancer Treatment and Diagnosis.
DTP’s functions can be broadly divided into:
- discovery and acquisition services,
- development and pathways to development
- information and resources for both NCI researchers and the extramural community, including academia and biotechnology and pharmaceutical companies
The success of DTP’s efforts is reflected in the fact that it has been involved in the discovery or development of a large percentage of the anticancer therapeutics on the market today.
|2015||Dinutuximab (NSC 623408)|
|2010||Eribulin (NSC 707389)
Sipuleucel-T (NSC 720270)
|2004||Cetuximab (NSC 632307)|
|2003||Bortezomib (NSC 681239)|
|1998||Denileukin diftitox (NSC 697979)|
|1996||Polifeprosan 20 with carmustine implant (NSC 714372)
Topotecan (NSC 609699)
|1995||All-trans-retinoic acid (NSC 122758)|
In 2009, NCI consolidated its anticancer drug discovery and development activities and resources into a single program called the NCI Experimental Therapeutics (NExT) program. The mission of NExT is to advance clinical practice and bring improved therapies to cancer patients by supporting the most promising new drug and biologic agent discovery and development projects. The NExT program is open to the extramural community, but proposed projects must be reviewed and approved for scientific merit. Entry into NExT can occur at any stage in the drug discovery and development pathway. Approved projects can take full advantage of NCI’s drug discovery and preclinical and clinical development resources.
The NExT program is currently supporting the clinical development of 43 investigational agents, 40 of which are molecularly targeted agents, with the goal of improving the treatment of adult and childhood cancers.
Experimental Cancer Models that More Closely Mimic Human Cancer
The NCI-60 Human Tumor Cell Line Screen
To support NCI’s anticancer drug discovery program, DTP established the NCI-60 human tumor cell line screen in 1990. This screen utilizes 60 different human cancer cell lines, representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney.
Over the years, the testing of tens of thousands of compounds using the NCI-60 cell line screen has generated the largest cancer pharmacology database in the world.
The screen continues to be a workhorse in cancer drug discovery and development today. Recently, it was used to screen combinations of just over 100 FDA-approved small-molecule drugs to identify combinations that might be more effective therapeutically than single agents. In this screen, approximately 5,000 drug combinations were tested, and two promising pairs are now being studied in adults with relapsed solid tumors in phase I studies at the NIH Clinical Center. One drug combination includes bortezomib and clofarabine (a nucleoside antimetabolite), and the other includes nilotinib (a tyrosine kinase inhibitor) and paclitaxel (a microtubule inhibitor).
New Human Cancer Models for Evaluating Treatments and Overcoming Resistance
As valuable a resource as the NCI-60 cell line panel has been, it does have limitations. One major limitation is that the panel includes only a few cell lines for just a few cancer types. It is not known how representative the cell lines are with respect to their corresponding cancer types. Indeed, these lines were generated in an era when establishing successful, long-term cell cultures was largely restricted to very aggressive cancers. Researchers also don’t know the degree to which cells in the lines differ genomically and functionally from the primary cancer cells from which they were derived. Moreover, the lines have not been annotated with clinical information, such as stage of disease at diagnosis, treatments given, response to therapy, and patient outcome.
One approach to creating new human cancer models is to transplant human tumor samples into immunodeficient mice to create what are called patient-derived xenografts (PDXs). In PDXs, interactions between cancer cells and stromal cells (fibroblasts present in the tumor microenvironment) are preserved to some degree. Because the tumor microenvironment can influence drug efficacy and the development of drug resistance, PDXs should be better models for developing anticancer therapies and screening drugs for precision medicine applications than earlier models. In fact, there is accumulating evidence that treatment responses observed in some parental tumors can be replicated in PDXs.
Because every tumor exhibits a unique constellation of genomic alterations, regardless of the tissue of origin, and genomic differences between tumors of the same type can lead to variability in drug responses, it is notable that PDX tumors have been shown to exhibit a high degree of genomic stability in relation to their parental tumors, even after transplanting tumor sections into new mice.
Developing large panels of PDX models for both biological studies and drug discovery and development should greatly enhance and accelerate our ability to deliver precision medicine interventions in the future. PDX models should also facilitate the study of tumor metastasis and drug resistance. New PDXs can be generated from metastatic and/or drug-resistant tumors, and differences between the original tumors and the metastatic and/or resistant tumors can be analyzed. Such studies may lead to new therapeutic strategies for treating metastatic and resistant disease.
Other improved human cancer models are now available because of advances in cell culture techniques. In one model developed by NCI-funded researchers, cancer cells are "conditionally reprogrammed" by co-culturing them in vitro with normal cell counterparts, such as fibroblasts, in the presence of an inhibitor of an enzyme called Rho kinase. This method enables the efficient establishment of cell lines from both normal cells and cancer cells. Cell lines established this way retain the essential molecular characteristics of the cells from which they originated.
Human cancer cells can also be grown as three-dimensional cultures as opposed to the traditional two-dimensional cultures. In one type of three-dimensional culturing approach, the cells are grown as multicellular aggregates, or spheroids, either in liquid medium or on scaffolds derived from natural or synthetic materials. Cancer cell spheroids display a number of the characteristics of an in vivo tumor, including the presence of chemical gradients (e.g., of oxygen, glucose, and metabolites) and the accumulation of DNA strand breaks. In terms of drug screening, there is evidence that cancer cells often respond differently to drug treatments when grown two-dimensionally (traditional cell lines and conditionally reprogrammed cell lines) versus three-dimensionally.
Another three-dimensional culturing method yields structures called organoids. These structures arise from cells in tumor specimens that exhibit the properties of cancer stem cells (self-renewing cells within a tumor that can give rise to all cell types found in that tumor).
Organoids form in the presence of a scaffold and essential growth factors. The cells in organoids differentiate to form multiple cell types and organize in patterns similar to those found in the tissue where the tumor developed. Organoids exhibit features similar to the tumors from which they were derived, including genomic features, and they can be propagated indefinitely. Co-cultivation of organoid-forming cells and fibroblasts from the same tissue of origin may yield structures even more representative of the original tumor, increasing their potential as platforms for drug screening and development.
Together, these new human cancer models should enhance our drug discovery and development efforts and increase our understanding of human cancer cell biology. Being able to molecularly characterize the tumor of every patient treated in an NCI-sponsored clinical trial and generate PDXs, conditionally reprogrammed cell lines, and organoid cultures from those tumors would greatly accelerate the evolution of precision medicine and its implementation into routine cancer care.