Targeting Fusion Oncoproteins in Childhood Cancers Network Pre-Application Webinar: Frequently Asked Questions (FAQs)

Questions about the TFCC Notices of Funding Opportunities

How does the TFCC Network relate to the current FusOnC2 Consortium?

The TFCC network is a follow-up to the Fusion Oncoproteins in Childhood Cancers (FusOnC2) Consortium but is a separate initiative. We hope that some of the investigators that were in the FusOnC2 Consortium will apply to TFCC, but there is no requirement or preference for FusOnC2 members. Investigators will be considered individually on their own merit. 

Can you please explain the focus on solid and brain tumors in the NOFOs, and not hematologic malignancies which are also common in children?

The NOFOs encourage applications on solid tumors and brain tumors, but this is merely an encouragement and not a restriction. Applications focusing on hematologic malignancies are allowed as well. From the programmatic perspective, solid tumors and brain tumors represent areas of urgent need given the paucity of effective new agents for these types of cancer. 

Are funding decisions based on both the scientific/technological merits and the administrative makeup of the research groups and admin teams?

Funding decisions will consider both peer review overall impact scores and programmatic components.

Would systematic characterization of oncofusions and small molecular screens by a cancer systems biology approach be responsive? Or do you envision more small-scale or single oncofusion centric?

This would likely depend on the nature of the experiments. Investigators should reach out to TFCC Program Directors, Drs. Keren Witkin, Malcolm Smith, or Joseph Agyin, to discuss this type of project. 

Can you elaborate on target eligibility with respect to “fusion oncoprotein targets for which clinical proof of concept has been achieved”? 

The wording in both RFAs is “fusion oncoprotein targets for which clinical proof of concept has been achieved will be excluded from eligibility.”

The interaction between menin and KMT2A is an example of a fusion oncoprotein target for which clinical proof of concept has been confirmed, as there are multiple menin inhibitors in clinical testing that have shown robust remission-inducing clinical activity.

A counter example is the use of BET inhibitors for NUT carcinomas. Given the limited efficacy of BET inhibitors for NUT carcinomas (i.e., low objective response rates and short durations of response), one can make a strong case that clinical proof of concept has not been confirmed for this approach to treating NUT carcinomas.  

Investigators should reach out to TFCC Program Directors, Drs. Keren Witkin, Malcolm Smith, or Joseph Agyin, to discuss the eligibility of individual fusion oncoproteins if they have questions. 

I work on a fusion oncoprotein found in young adults as well as children. Is this acceptable?

In general, this should be acceptable. Investigators should reach out to TFCC Program Directors, Drs. Keren Witkin, Malcolm Smith, or Joseph Agyin, to discuss the eligibility of individual fusion oncoproteins.

Are there advantages or disadvantages if the Principal Investigators (PIs) are all from the same institution?

This is neither an advantage nor disadvantage for the application, assuming that the application is able to document that the PIs selected bring the requisite level of expertise to successfully address the research program proposed. It will be important to thoroughly describe the expertise of each investigator, to explain what capabilities they will contribute to the project, and to justify their role, percent effort and any salary that may be requested.

Questions about TFCC U01 Research Projects

Do U01 applications in response to RFA-CA-23-036 need to be Multiple Principal Investigators (MPI) applications?

No. The determination of single PI versus MPI should be based on what is appropriate for the project being proposed. 

Should U01 applications focus on one fusion oncoprotein or cancer or should they have a broader scope covering more than one fusion oncoprotein?

This is up to the investigator, keeping in mind the feasibility of the work being proposed, given the budget and the timeline of the award. The U01 is similar in size to an R01, and the Principal Investigator needs to take that into consideration.

Given the U01 network mechanism, is it likely that more than one application from a given institution would be viewed unfavorably?

While multiple applications from the same investigator are discouraged, there is no limit to the number of applications from the same institution and this is unlikely to affect funding decisions. 

Could you elaborate what stage of discovery the U01 applications should focus on and how much preliminary data is expected? For example, would characterizing protein interaction networks using novel technologies be considered, or one would need to already have candidates and investigate into those?

We are not restricting the U01 mechanism to any particular stage of discovery. While applications will be reviewed in a Special Emphasis Panel that will be trained for these specific RFAs, investigators should keep in mind the challenge of showing feasibility for exploratory experiments. Discovery-based experiments should be based on preliminary data to the extent possible and should address feasibility issues. 

Are chemistry-centric U01s encouraged?

The U01 NOFO does not emphasize chemistry-centric U01s. The U01 NOFO is meant for mechanistic studies on the function of fusion oncoproteins and how they drive pediatric cancers. Investigators should reach out to TFCC Program Directors, Drs. Keren Witkin, Malcolm Smith, or Joseph Agyin, to discuss this type of project. 

In the U01 mechanism, if a proposal has outside collaborators, does the typical inclusion of indirect costs into the subcontracts apply, or are the collaborating institutions funded directly by the NCI?

All awards will be made to the contact institution. If they have sub-awards, the indirect costs on the subcontracts are not included in the 325k direct cost budget. This is stated in the budget section of the U01 NOFO. 

With respect to the U01, is genome editing to model the gene fusion is acceptable?

Gene editing to model gene fusions could be an acceptable approach. Investigators should reach out to TFCC Program Directors, Drs. Keren Witkin or Malcolm Smith, to discuss this type of project. 

What was the rationale for making this a U01 mechanism vs. an R01 mechanism? 

From an NIH perspective, the U01 mechanism was selected because program staff will support a group of investigators who will be working together on common goals and will meet on a recurring basis to discuss shared goals, approaches, and challenges. This also facilitates leveraging other NIH programs to form partnerships for joint meetings, projects, and research resources. Please read the cooperative language in the NOFOs.
 

Question about UM1 Next Generation Chemistry Centers (NGC) for Fusion Oncoproteins

For the UM1, what is the difference between research projects (2-4) and research groups in section B?

The research projects and research groups should be considered analogous; they are being used as synonymous terms. 

For the UM1, is it likely that the center needs groups in structural biology, computer-aided drug discovery, and medicinal chemistry besides 2-4 research projects?

Expertise in structural biology, computer-aided drug discovery, and medicinal chemistry, if needed, is expected to be an integral part of one of the 2-4 Research Groups described in the Research Strategy (Subsection B), based on the scope of work proposed and the specific needs of the NGC Center.

For the UM1, are synergies between research projects required or the subject of evaluation by the review committee?

The UM1 grant mechanism involves complex research, and all of the components in a UM1 grant have to work together to meet the goals. There needs to be justification for how each of the research programs proposed in the application are essential to meeting the overall research objectives of the NGC center.

For UM1 applications in response to RFA-CA-23-037, would a peptide-based agent meet the criteria?

The NOFO defines small molecules in a distinct way. A peptide-based agent may be responsive if it meets our definition, i.e., chemically synthesized, drug-like compound with molecular weight <2000 Da and able to cross cell membrane to modulate fusion oncoprotein function. Please refer to RFA-CA-23-037 for more information. 

Is genome editing considered a viable strategy for the UM1?

No, genome editing would not be acceptable for the UM1. The focus is on the development of small molecules.