The lack of well-validated and widely accepted cell lines derived from intestinal carcinoid and pancreatic neuroendocrine tumors is a significant barrier for research and development of new therapies. The Neuroendocrine Tumor Research Foundation therefore wishes to stimulate a concerted effort to create a “collection” of well-characterized cell lines that faithfully replicate tumor characteristics and genetics. The Foundation has partnered with the Rare Cancer Research Foundation (RCRF), a foundation dedicated to curing rare cancers through strategic investments and innovative collaborations, and the American Type Culture Collection (ATCC), the world’s largest non-profit cell line repository, to establish a Neuroendocrine Tumor Cell Line collection in their catalog.
This challenge requires written documentation, detailed description of each cell line, and sample delivery.
This Challenge is intended to encourage innovative approaches to establishing new cell lines from primary tumors that grow slowly in vivo and to publicize new methods as well as availability of the new cell lines for broad, unrestricted use. The NET Research Foundation therefore wishes to stimulate a concerted effort to create a “collection” of well-characterized cell lines that faithfully replicate tumor characteristics and genetics. To stimulate development of cell lines, NETRF is running a competition for creation of intestinal carcinoid and pancreatic neuroendocrine tumor cell lines. Developers of intestinal carcinoid cell lines will receive $250,000 each and developers of pancreatic neuroendocrine tumor cell lines will receive $100,000 each.
To be eligible for the prize(s), the submitted cell lines must be:
- Approved by the Neuroendocrine Tumor Research Foundation, according to the criteria specified in the Detailed Description & Requirements, and
- Deposited into the ATCC repository for unrestricted distribution to qualified investigators under an agreement approved by the Neuroendocrine Tumor Research Foundation.
Discover how to submit your cell lines in the Detailed Description & Requirements of the Challenge.
Detailed Description and Solution Requirements
The majority of neuroendocrine tumors can be divided into two classes: carcinoid and pancreatic neuroendocrine tumors. Carcinoid commonly refers to neuroendocrine tumors that originate in the gastrointestinal (GI) tract, lungs, appendix and thymus, although they can also occur in the lymph nodes, brain, bone, gonads (ovaries and testes) and skin. Carcinoid tumors are usually indolent (slow-growing) by nature and develop over the course of many years. However, aggressive, fast-growing forms of carcinoid cancer also exist.
Neuroendocrine tumors are classified as rare cancers. Recent studies have determined that 4 to 5 out of every 100,000 people are diagnosed yearly with a neuroendocrine tumor and that there are over 100,000 people currently living with neuroendocrine tumors within the United States (Yao et al., 2009). For reasons not well understood, the incidence of these cancers is rising. Since most individuals with neuroendocrine tumors are asymptomatic until the tumors metastasize, the average time between tumor development and diagnosis is between 5 to 10 years (Vinik, 2008; Vinik et al., 2009). Survival rates for individuals with neuroendocrine cancer vary and depend on tumor type, location, extent of metastases, and many other factors. Currently, surgery is the only cure for localized tumors (those which have not spread) and there is no cure for metastatic neuroendocrine cancer (Yao, 2007).
This Challenge is intended to encourage development of intestinal carcinoid and pancreatic neuroendocrine tumor cell lines.
Vinik, A. I., Feliberti, E., Perry, R., Nakave, A. (2008). Diffuse Hormonal Systems and Endocrine Tumor Syndromes. Retrieved from: http://www.endotext.org/section/guthormone
Vinik, A. I., Silva, M. P., Woltering, E. A., Go, V., Warner, R., Caplin, M. (2009). Biochemical Testing for Neuroendocrine Tumors. Pancreas, 38(8), 876-899. Retrieved from:http://www.ncbi.nlm.nih.gov/pubmed/19855234.
Yao, J. C. (2007). Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best practice and research, clinical endocrinology and metabolism, 21(1), 163-172. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17382271.
Yao J. C., Hassan, M., Phan, A., Dagohoy, C., Leary, C., Mares, J. E., Abdalla, E. K., Fleming, J. B., Vauthey, J. N., Rashid, A., Evans, D. B. (2008). One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical Oncology, 20(26), 3063-3072. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/18565894.
For more background information on intestinal carcinoid and pancreatic neuroendocrine tumors, please visit the Neuroendocrine Tumor Research Foundation website.
Investigators who create one or more immortal cell lines from intestinal carcinoid and/or PNET tumors are invited to submit the cell line(s) for prompt validation, to establish eligibility for the prize(s), and to initiate the process for repository deposit. Creators may submit multiple cell lines however NETRF reserves the right to reject excessive applications. Only investigators who the Neuroendocrine Tumor Research Foundation has funded after 2011 to create cell lines are ineligible for the Prize.
To achieve standards of authenticity (see Inclusion Criteria below), all cell lines will be validated in a contract research laboratory appointed by the Neuroendocrine Tumor Research Foundation. Cell lines submitted for validation and prize eligibility will not be distributed without the permission of the submitting investigator.
Submission and validation of cell lines for inclusion in the collection will proceed as follows:
2) A Foundation representative will contact you to coordinate transfer of the cell line to a lab designated by the Foundation for validation and characterization. If necessary, the Foundation will help arrange a Material Transfer Agreement between your institution and the designated laboratory governing the use of your cell line. Any and all Depositor Agreements that are entered into between ATCC and Third Party depositors will be non-exclusive, unless otherwise agreed to by ATCC and such Third Party depositors.
3) Submit early passages of the cell line(s) and the relevant data, tissue, or tissue derivatives (see information in Submission Requirements and Inclusion Criteria below) to the testing laboratory designated by the Neuroendocrine Tumor Research Foundation.
4) Cell lines will be validated using some or all of the following approaches: gene expression profiling, high-density genotype arrays, immunoblotting, and potentially others, with the goal to verify tissue origin and fidelity to the original tumor. Cell lines will also be checked for mycoplasma contamination. Data generated for the purpose of validating cell lines will be shared with the submitting investigator and may be used in future publications.
5) If cell line characteristics are compatible with their origin in carcinoid tumors or PNETs, they will be considered for inclusion in the collection. The Foundation will notify the submitting investigator about the outcome of the validation studies.
6) Investigators whose cell lines are selected for inclusion in the collection, and their Institutions, must execute a Material Deposit Agreement (Appendix B, available upon selection) to deposit the cell line(s) with ATCC (“Deposit Agreement”).
7) Upon finalizing a Deposit Agreement and depositing of validated cell lines into the ATCC repository, the Foundation will issue an award letter and payment form offering an unrestricted prize in the amounts specified in Section I for cell lines deposited into the collection. Prizes will be issued to the investigators’ Institution, for distribution according to the Institution’s rules and policies. Investigators are encouraged to review and discuss those policies with their Institute officials before submitting the Letter of Intent for cell lines.
8) Investigators must complete and return the payment form before the Foundation will issue a check to the “Fiscal Officer” address identified on the payment form.
9) Please call 617-948-2514 or email email@example.com with questions about any aspect of this prize and announcement.
For cell lines to be eligible for the prize(s), the creator(s) must submit the following:
- At least three (3) frozen vials, each containing at least 5 million cells in a 1 mL volume from each new cell line. The storage solution should contain 10% dimethyl sulfoxide (DMSO), diluted either in fetal bovine serum alone (90% FBS) or the appropriate growth medium supplemented with 30% FBS. Applicants are encouraged to confirm that >80% of the cells survive thawing after the cryopreservation protocol.
- A de-identified (anonymized) Pathology Report from the tumor of origin; 10 unstained histologic slides that represent the bulk tumor; and a frozen or paraffin-embedded tissue sample of the tumor from which the cell line was derived.
- Information about the tumor from which the cell line was derived:
- Anatomic location of the intestinal carcinoid tumor or PNET
- Whether the tumor was primary, recurrent, or metastatic
- Dated and de-identified (anonymized) operative report
- Biochemical, cytogenetic, and immunophenotypic data, if available
- Samples of DNA extracted from (a) the tumor from which the cell line was derived, and (b) non-tumoral DNA from the same patient (e.g., mononuclear blood cells, buccal swab, uninvolved distant tissue from a surgical specimen). These DNA samples will be used to verify that the genetic profile of the cell line resembles the bulk tumor and not an outgrowth of normal cells or a rare, non-representative clonal sub-population (clones that represent a significant tumor population will be considered eligible).
- A copy of the Informed Consent form used to collect the tumor from which the cell line was derived. This Informed Consent must permit use, storage, and distribution of cell lines for all research and development purposes and specify that the donor waives the right to profit from any research on, or commercial products derived from, the cell lines.
- A detailed description of each cell line, including:
- Methods for initial tumor dissociation and cell culture
- Approximate number of passages/culture history, including time period over which cells were passaged
- Significant changes in phenotype or subpopulations during passage
- History of microbial contamination and anti-microbial treatment
- If known: Data regarding phenotype (e.g., properties in soft agar or xenografts), somatic copy number alterations, transcript and protein expression, any other available validation or corroborative data
- Instructions for culturing the cell line, including product information for media and other reagents.
- Information about the patient from which the cell line was derived (if available)
- Gender, age at diagnosis, race
- Treatment history: prior surgery, chemotherapy, or radiation
- Patient outcome: disease in remission or active? Alive or deceased?
- A letter from the appropriate Institute official stating that
- The creator(s) are employees who are eligible to participate in the competition.
- The Institute will manage distribution of the prize among eligible staff, according to Institute policies. The Foundation will not adjudicate disputes between the creator(s) of any cell line and their respective Institutes.
- Informed Consent conformed to Institute policies and the cell line may be distributed to other investigators without restriction
- The Institute will execute a Materials Transfer Agreement with the ATCC repository that permits unrestricted distribution of cell lines.
Cell line(s) will be evaluated for inclusion in the collection and eligibility for a Prize according to the following criteria:
|Confirmed pathologic diagnosis of intestinal carcinoid tumor or PNET||The original tumor has accepted morphologic criteria for these diseases and stains with Synaptophysin and/or Chromogranin antibodies by immunohistochemistry.|
|Human species||Karyotype, human-specific PCR products, or hybridization to human oligonucleotide array|
|Clonal genome aberrations consistent with those reported in carcinoid tumor or PNET||Karyotype, high-density genotyping arrays, or exome sequencing|
|Genotype does not match known cell lines||Short tandem repeat (STR) profiling and verification against databases of existing cell lines|
|Cell line is immortal||At least 50 population doublings|
|PLUS at least two of the following|
|Genome alterations match the original tumor||High-density genotyping arrays and/or sequencing of the genome, all or selected exons, or specific mutations|
|Expresses lineage-restricted genes||Polymerase chain reaction, transcript profiling by hybridization arrays or RNA sequencing, immunofluorescence, or immunoblotting|
|Neuroendocrine morphology and cellular features||Light and/or electron microscopy|
Validation studies will be conducted at the Foundation’s expense. Results will be shared with submitting investigators and included in cell line characteristics submitted together with the cell line(s) to the ATCC depository. Submitting investigators are encouraged to publish the results of validation studies.
In addition to satisfaction of the scientific criteria listed above, the Foundation has the following guidelines and expectations for inclusion of cell lines in the Collection.
- Proper Informed Consent must have been obtained from the patient to allow use, storage and distribution of the cell line for all research and development purposes. No profit from any commercial products derived from the cell line(s) shall be returned to the patient.
- Data generated in the course of characterizing cell lines will be shared only with submitting investigators, the Neuroendocrine Tumor Research Foundation, and any impartial scientists the Foundation may request to offer expert opinions about cell line validity. These data will be kept confidential until submitting investigators waive confidentiality. Upon inclusion in the ATCC repository and acceptance of a Prize, all data associated with the cell line and available to the Foundation must be made public and distributed with the cell line.
- The Foundation encourages creators to publish the results of research that led to the development and characterization of the new cell line(s) in peer-reviewed journals, preferably with open access. If a journal imposes additional charges for Open Access, beyond routine page charges, the Foundation will consider bearing that additional expense. At the request of submitting investigators, the Foundation will embargo specific data obtained in characterization of cell lines for up to six (6) months to give the creator an opportunity to publish on the creation and characterization of the cell line.
- Submitting investigators and their Institution must enter into a Deposit Agreement with ATCC. This Agreement must be approved by the Neuroendocrine Tumor Research Foundation and permit unrestricted distribution of cell lines to academic and commercial laboratories at charges that reflect industry standards and those for other cell lines in the same collection.
- Upon an Institution’s acceptance of a Prize, the Foundation will be permitted to publicize the name of the Institution and/or creator, the amount of the Prize, features of the cell line(s), and details on their availability from the chosen repository.
A. Award Process
The decision to include a cell line in the collection and to award Prizes in the amounts specified in Section I will be made by the Neuroendocrine Tumor Research Foundation’s Board of Directors, based on the recommendation of expert advisors, the availability of funding, and other pertinent factors. The Foundation will consider genetic and biological characteristics of the cell line as well as accompanying data regarding the tumor from which the cell line was derived.
The Foundation will notify investigators in writing whether or not cell line(s) are selected for inclusion in the collection. Upon (i) validation, (ii) selection for inclusion in the collection, (iii)execution of a Deposit Agreement, and (iv) deposit of the cell line into a public repository of the Foundation’s choosing, the Neuroendocrine Tumor Research Foundation will issue an Award Notification letter and payment form offering an unrestricted prize in the amount specified in Section I.
B. Acceptance of Award
Investigators and Institutions accepting an award by signing the Award Notification letter and depositing funds disbursed by the Foundation will be bound by the terms and conditions attached to the Award Notification letter. Each prize will be awarded on the terms and conditions outlined herein.
C. Disbursement Policy
The Prizes are intended to incentivize and reward investigators for contributing cell lines for unrestricted distribution toward development of new therapies for carcinoid tumors and PNETs. They will be made as unrestricted awards to the creator’s Institution, to be shared with the creator(s) in accordance with Institute policies. Payments to the submitting investigator’s Institution will be made by check, unless otherwise requested by an authorized Institute official. Checks will be mailed to the “Fiscal Officer” identified on the payment form.
Upon acceptance of one or more Prizes, the creator and the creator’s Institution will indemnify and hold harmless the Neuroendocrine Tumor Research Foundation, its Board, officers, agents, advisors and constituents from any claim, judgment, award, damage, settlement, liability, negligence or malpractice arising from any activities related to this award.