STAFF HIGHLIGHT: Talent and Teamwork — The Foundation of DCTD’s Biological Testing Branch

The Biological Testing Branch (BTB) in DCTD’s Developmental Therapeutics Program operates out of the NCI Frederick, providing preclinical tools of the highest quality for the evaluation of new agents for people with cancer. Simply put, BTB provides an essential service within DCTD by developing and maintaining animal and human tumor cell lines and patient-derived models. However, the success of this essential program is anything but simple; it requires that an enormously complicated group of technical, logistical, and administrative components work together perfectly.

Several BTB staff, including BTB’s Branch Chief, Dr. Melinda Hollingshead, describe their roles in BTB. From their words, it becomes apparent quickly that the crucial foundations of BTB’s operational success are talent and teamwork.

Michelle Ahalt-Gottholm, Program Specialist

I coordinate the research protocols for the contract staff and handle all the paperwork for the experiments. Our animal care staff are dedicated and look after the well-being of the mice in the experiments every day. We stay aware of issues related to the individual models, the health of the animals, and our mouse colonies.

We may need to alert staff about models if there are issues. For example, when we do drug studies and look at the effects of the agents on the animals and possible toxicity, we determine how much supportive care the mice need. If we’ve increased dosing too much and record a loss of body weight, we see what the mice look like, and that may differ from what we’re tracking and recording.

We can see toxicity just by implanting tumors into mice, but when adding cancer drugs on top of that, it can be harder on the well-being of the mice. It’s great when the drugs we’re testing work, and the mice “age out” of the study due to their tumors being cleared.

Tara Grinnage-Pulley, DVM, PhD, Veterinary Medical Officer

Much of my work revolves around monitoring the health and well-being of the animals in the labs and in the breeding colonies. We keep close track of the health of the mice. I go through each building once per week to look at the animals and talk to the animal care and technical staff. I may encounter something minor like a wound on an animal or something major like a sickness. If an animal is sick, we’ll determine if it’s treatable or if the implanted tumor sample can’t be used.

I really want to commend the animal breeding staff. I ship the mice, but the staff that breed the mice and maintain the colonies are the backbone of the research effort, ensuring that we have sufficient mice to do the studies.

Sergio Alcoser, PhD, Biologist

My lab tests the tissue harvested from the xenograft models, which result from the patient tumor cells implanted months before. The animal technical care staff give tissue to us and some to the Molecular Characterization Laboratory (MoCha) at the Frederick National Laboratory for Cancer Research (FNLCR) so they can evaluate tumor histology and perform genomic characterization studies. We extract the DNA from the tumors to confirm that it is of human origin and quantify the amount of mouse tissue that may be incorporated.

We look at the resulting data to see if it makes sense for the tumor being grown. For example, do all the kidney tumors cluster together based on our genetic data, or does one seem different? If a mistake is made, possibly by mixing up the tubes, we verify what happened and make corrections before the tumors are sent out to researchers who request them. There is a lot of back and forth between groups involved in this work and Michelle does a great job tracking these complicated details!

Melinda Hollingshead, DVM, PhD, Branch Chief

I do a little of everything to make sure the projects in BTB move forward. I focus on overseeing the generation of PDX tumors, distribution of the models, ensuring the repository has samples, and generating drug studies for DCTD. However, we rely on a lot of people for BTB’s work, and there isn’t one specific individual in BTB who is responsible for our branch’s success. Each member of BTB’s staff does different but overlapping tasks, and each person is critical and contributes to the final high-quality products.

I’d like to recognize Michelle Eugeni, the oncology nurse who works with participating clinical sites to secure patient samples for the generation of new PDX models, Dr. Bethany Asare, who manages the DCTD Tumor Repository that sends out hundreds of cell lines and tumor fragments each year, and Dr. Kim Klarmann, who heads the effort to generate “liquid tumor” PDX models. We have outstanding animal care staff and an excellent animal breeding program, which is the starting point to make the models. We maintain the animals, and tweak processes as necessary (e.g., if we see things are working or not, we adjust accordingly). The diverse efforts of many people combine to make all the work we do possible.

A great example of BTB’s teamwork is when our staff demonstrated a clotting syndrome was developing secondarily to the tumors that were implanted in the mice, and the animals were dying from the clots. Now we have a model for these clots, and that is because Tara generated the samples to confirm what we saw, Sergio showed there were human samples present, and Michelle did all the tracking of animals. These folks plus all other people who support us make BTB successful.

During the beginning of the COVID-19 pandemic, when most places closed around the US and NIH, we still needed staff in the labs every day. We adapted to the situation and didn’t stop caring for the animals, doing experiments, and breeding the mice. There were fewer people onsite at a time, but we still needed to get the work done and never stopped passaging cells. If we did, we would not have the data we have today.

Everyone in the BTB deserves a lot of credit; they persevere because they see something bigger than their personal reward. We’ve got several long-term staff — they’ve been at NCI for years and years — and they’re here because they want to help people with cancer live longer and better lives.

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A NOTE FROM DR. JERRY COLLINS
Former Associate Director, Developmental Therapeutics Program
On the important publicly available data in the ROADMAPS publication

Dr. Hollingshead and her colleagues are providing a new preclinical tool to the cancer research community — the “ROADMAPS” (Responses to Oncology Agents and Dosing in Models to Aid Preclinical Studies) database. This publicly available resource provides data on doses, schedules, vehicle formulations, responses, and toxicity for 70 FDA-approved oncology drugs and 140 different xenograft models collated from decades of BTB research. Published in Cancer Research, this invaluable dataset is intended to inform the design of clinically relevant, tolerable single and combinatorial regimens in preclinical mouse models.

The data reported and organized in this paper resulted from the accumulated efforts of multi-talented federal employees and contractors working together over a period of 50 years. BTB’s work is at the core of this experimental effort.

SPOTLIGHT: DCTD Diversity, Equity, Inclusion, and Accessibility (DEIA) Update

DCTD is committed to ensuring DEIA in our workforce, hiring practices, and workplace culture. To further this commitment to DEIA, DCTD hired Dr. Leah Hubbard as Chief Diversity Officer (CDO) for the division. This new position will function concurrently with her position as a Program Director in DCTD’s Translational Research Program.

In her role as CDO, Dr. Hubbard will:

1) serve as an advisor to the DCTD leadership to enhance DEIA in the division,
2) support programs to improve DEIA in recruitment, hiring, and retention of DCTD staff,
3) support programs to promote DEIA in the DCTD workplace culture, and
4) serve as the point of contact for questions and concerns from DCTD staff regarding DEIA.

Through Dr. Hubbard’s position as CDO and the active support of DCTD leadership, our division will ensure our workplace is an environment that is welcoming and supportive of its staff in all areas of the division. Moreover, we are committed to ensuring our workplace is free of racism, harassment, discrimination, and bullying.

Over the next 12 months, DCTD will focus on enhancing DEIA by:

1) generating best practices resources for DCTD hiring managers and selection committees to use during the hiring process, and
2) assessing the workplace climate and culture among DCTD staff to identify areas for improvement and create new programs.

Dr. Hubbard has been promoting DEIA efforts throughout NIH and NCI through leadership roles on NIH UNITE Committee E, NCI Equity Council Working Group 3, the NIH Program Leadership Committee UNITE Working Group, the NCI Racial and Ethnic Equity Plan Implementation Team, and the Eight Changes for Racial Equity (8CRE). Additionally, Dr. Hubbard received two NIH Director’s Awards, an NCI Director’s Award, and an NIH Special Act/Service Award for her activities in NIH UNITE, 8CRE, and the NCI Equity Council Working Group 3.

SPOTLIGHT: 2^nd Annual NIH Integrative Medicine and Women’s Health Webinar

National Women’s Health Week (NWHW) begins on Mother’s Day each year and reminds:

• women to prioritize their wellness
• biomedical investigators to consider the importance of including sex as a biological variable in the design, analysis, and reporting of research
• the medical community to share tips and tools to help women focus on their health and create personal wellness plans

The Trans-NIH Committee on Integrative Health, in partnership with ^co-sponsoring offices and centers, contributes to NWHW by hosting annual webinars on topics in women’s health to improve the lives of all women, including those living with, or having survived cancer. The topics incorporate integrative modalities in disease prevention, symptom management, and adjunctive treatment. The goals of the webinar are to:

• discuss evidence-based comprehensive women’s healthcare, including those modalities relevant to integrative health, by inviting expert speakers from government, academia, and the community
• assess the current state-of-the-science of topics in women’s health
• identify research gaps through post-symposium white papers

ORWH identified substance use disorders (SUD) in women as a subject of high morbidity and priority. Farah Zia, MD, DCTD’s Office of Cancer Complementary and Alternative Medicine, led a *webinar planning and host committee to convene the 2nd Annual Webinar on May 11, 2022: “Integrative Health Modalities for the Treatment & Relapse Prevention of SUD in Women.”

The keynote speaker, Dr. Elizabeth Krans, University of Pittsburgh Medical Center, Magee Women’s Hospital, discussed healthcare delivery approaches for pregnant persons with SUD, empowering patients in recovery, and how pregnant women with SUD face profound social, economic, and physical challenges that require a multi-faceted approach to healthcare delivery. The remaining speakers addressed:

• Using mindfulness in women’s substance use treatment
• Biobehavioral mechanisms and clinical outcomes for women with chronic pain, opioid misuse, and opioid use disorder
• Understanding the role of gender in mental health and SUD
• Acceptability and feasibility of yoga among women in SUD recovery
• Acupuncture for women in SUD recovery
• Entrepreneurial mindset development program for women in recovery

ORWH concluded with a panel discussion that emphasized the need for:

• Multi-disciplinary approaches to treat SUD in women
• Approaches that consider both physical dependance and co-occurring social and emotional challenges (e.g., depression, anxiety, post-traumatic stress disorder, etc.)
• Continued clinical research with larger trials and better methodology
• A meeting white paper to provide conclusions and analysis informing the research community of future needs

^ Co-Sponsoring Offices and Centers
NIH Office of Research on Women’s Health (ORWH)
National Center for Complementary & Integrative Health (NCCIH)
NIH Pain and Palliative Care Service

*2022 Webinar Planning & Host Committee
Farah Zia, M.D (NCI/NIH)  ziaf@mail.nih.gov
Ann Berger, M.D. (CC/NIH)  aberger@cc.nih.gov
David Shurtleff, Ph.D. (NCCIH/NIH)  david.shurtleff@nih.gov
Sarah Temkin, M.D. (ORWH/NIH)  sarah.temkin@nih.gov
Dan Xi, Ph.D. (NCI/NIH)  xida@mail.nih.gov

NEWS ACROSS DCTD

Two Decades of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

The BMT CTN recently reached a milestone — 20 years of contributions to the field. The BMT CTN was established in 2001 and was renewed in 2006, 2011, and 2017 with funding from the National Heart, Lung, and Blood Institute (NHLBI) and the NCI. The BMT CTN convenes a State of the Science Symposium every 7 years to establish a roadmap for future trial concepts incorporating research advances. The network has conducted definitive lymphoma and multiple myeloma trials based on input from these meetings.

The BMT CTN infrastructure facilitates participation of a large network of centers in trials available to patients in all regions of the US. The network conducts multi-institutional clinical trials to evaluate promising cellular therapies like hematopoietic cell transplantation, cellular vaccines, and chimeric antigen receptor T-cells for people facing life-threatening disorders.

For more information on the BMT CTN, contact Drs. Rich Little (littler@mail.nih.gov) or Lori Henderson (hendersonlori@mail.nih.gov) from NCI or Nancy Difronzo (difronzon@nhlbi.nih.gov) from NHLBI.

Responses to Oncology Agents and Dosing in Models to Aid Preclinical Studies (ROADMAPS)

The NCI’s  Biological Testing Branch (BTB), led by Dr. Melinda Hollingshead, has compiled response and toxicity data from more than 30 years of BTB preclinical studies evaluating anti-cancer agents. These efforts include testing investigational agents, many of which have received FDA approval, and identifying novel applications for existing drugs. NCI recently made this searchable, expansive data set available to the extramural research community. It includes more than 3,000 unique combinations of tumor models, drugs, and dosing regimens in mice. ROADMAPS offers a consolidated resource for dosing information and response data and is described in a recent publication in Cancer Research (Hollingshead, et al; 2022).

DCTD’s Radiation Research Program Presents NCI Workshop on Neutron Capture Therapy (NCT) for Cancer

Because of recent technological advances, medical centers can house relatively small (comparable to proton therapy units), accelerator-based neutron sources. This new development has strengthened interest in developing and testing new NCT delivery agents in clinical trials. NCI recently convened a workshop to assess the state of NCT and discuss the best models/methods for preclinical and clinical research. Read more and access the three days of recordings.

Webinar Series — Novel Chemical Approaches for Targeting Fusion Oncoproteins

DCTD and the Division of Cancer Biology are co-leading a weekly webinar series that started on August 19, 2022 and will continue through October 21, 2022. The goal of the series is to enhance understanding within the NCI and the research community of opportunities for targeting fusion oncoproteins through emerging chemoproteomic methods. Registration and more information are available on the NCI event site.

This webinar series is open to the public and free to attend. Recordings of individual sessions will be posted after completion of the session.

Contacts  sharad.verma@nih.gov or witkinkeren@mail.nih.gov

NCI Cancer HealthCast Podcast Featuring Larissa Korde, MD

A recent Cancer HealthCast podcast features Dr. Larissa Korde, Cancer Therapy Evaluation Program, discussing the crossroads between cancer and COVID-19 in the NCI COVID-19 in Cancer Patients Study (NCCAPS). Listen to all Cancer HealthCast episodes.

Career Confessions from Cancer Data Scientists

CBIIT asked eight NCI data scientists to share their advice and career journeys to help new investigators answer the question: What should I know to start my career in cancer data science? Dr. Yuri Kotliarov a computational biologist in the Biometric Research Program was one of the eight participating NCI scientists to share their career journey. In CBIIT’s recent Cancer Data Science Pulse blog, Dr. Kotliarov shares the career journey that took him from researching super conductors to supercomputing for cancer research.

Co-Clinical Imaging Research Program (CIRP) Annual Virtual Meeting 2022

The Cancer Imaging Program convened the annual CIRP meeting in June this year. The meeting’s mission was to:

• Review the progress of the CIRP program
• demonstrate CIRP web resources
• identify challenges in the four essential areas of the CIRP (animal models, co-clinical trials, quantitative imaging, and informatics)
• seek solutions to integrate data, harmonize protocols, and/or standardize methodology

Read more about the network and this year’s meeting, including the meeting topics.

DCTD at AACR and ASCO in 2022

DCTD-supported research was presented at the 2022 AACR and ASCO annual meetings. See the schedule of presentations containing DCTD staff speakers and co-authors at both meetings:
Schedule of DCTD Presentations at AACR 2022
Schedule of DCTD Presentations at ASCO 2022

Jim Doroshow, MD, DCTD Director, was a panelist in the AACR Annual Meeting forum “Breaking Down Silos: If We Did It During the COVID Pandemic, Why Not for Cancer?” chaired by Dr. Antonio Ribas. Following the Annual Meeting, AACR Meeting News published a summary of the panel and Dr. Doroshow’s presentation.

NCI-MATCH Contributes to FDA Approval

Along with a few other studies, NCI-MATCH subprotocol H contributed data that led to the FDA accelerated approval of dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. Read more about the FDA approval of this combination from the FDA and in NCI’s Cancer Currents blog.

Selected Publications and NCI Cancer Currents Blog Posts

Publications

Tatum JL, Kalen JD, Jacobs PM, et al. 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography as an In Vivo Biomarker of inhibition of CDK 4/6-Rb pathway by Palbociclib in a patient derived bladder tumor. J Transl Med. 2022 Aug 18;20(1):375.

Hong JA, Vikram B, Buchsbaum J, et al. The state of preclinical modeling for early phase cancer trials using molecularly targeted agents with radiation. Radiat Res. 2022 Aug 17. Online ahead of print.

Chihara D, Lin R, Flowers CR, et al. Eary drug development in solid tumors: analysis of National Cancer Institute-sponsored phase 1 trials. Lancet. 2022 Aug 13;400(10351):512-521.

Olaku, O, Conley BA, Ivy, SP, et al. Survey of Lifestyle, Past Medical History and Complementary and Alternative Medicine Use Among Adult Patients Participating in the National Cancer Institute’s Exceptional Responders Initiative. Transl Oncol. 2022 Aug 6;25:101484. Online ahead of print.

Yantian Zhang and Robert Nordstrom. Celebrating Contributions of Imaging Technology to Fight against Cancer at the 50th NCA Anniversary. Radiol Imaging Cancer. 2022 Aug;4(5);e220085.

Desai AV, Gilman AL, Ozkaynak MF, et al. Outcomes Following GD2-Directed Postconsolidation Therapy for Neuroblastoma After Cessation of Random Assignment on ANBL0032: A Report From the Children’s Oncology Group. J Clin Oncol. 2022 Jul 15;JCO2102478. Online ahead of print.

Bedard PL, Li S, Wisinski KB, et al. Phase II Study of Afatinib in Patients with Tumors with Human Epidermal Growth Factor Receptor 2-Activating Mutations: Results From the National Cancer Institute-Molecular Analysis for Therapy Choice ECOG-ACRIN Trial (EAY131) Subprotocol EAY131-B. JCO Precis Oncol. 2022 Jul;6:e2200165.

Naqash AR, Moey MYY, Tan X-WC, et al. Major Adverse Cardiac Events with Immune Checkpoint Inhibitors: A Pooled Analysis of Trials Sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program. J Clin Oncol. 2022 Jun 4. Online ahead of print.

Thanarajasingam G, Minasian LM, Bhatnagar V, et al. Reaching beyond maximum grade: progress and future directions for modernising the assessment and reporting of adverse events in haematological malignancies. Lancet Haematol. 2022 May;9(5):e374-e384.

Yang SX, Hewitt SM, and Yu S. Locoregional tumor burden and risk of mortality in metastatic breast cancer. NPJ Precis Oncol. 2022 Apr 5;6(1):22.

NCI Cancer Currents Blog

Dabrafenib-Trametinib Combination Approved for Solid Tumors with BRAF Mutations. July 21, 2022.

For Some Kids with Brain Cancer, Targeted Therapy is Better than Chemo. June 29, 2022.

New Drugs Raise Old Questions about Treating Cancer during Pregnancy. May 25, 2022.

FUNDING UPDATES

Title	Announcement Number	First Available Due Date	Expiration Date	Activity Code
Cancer Adoptive Cellular Therapy Network (Can-ACT) for Adult Cancers (Clinical Trial Required)	RFA-CA-028	September 28, 2022	July 1, 2023	UG3/UH3
Cancer Adoptive Cellular Therapy Network (Can-ACT) for Pediatric Cancers (Clinical Trial Required)	RFA-CA-029	September 28, 2022	July 1, 2023	UG3/UH3
Cancer Adoptive Cellular Therapy Network (Can-ACT) Coordinating Center	RFA-CA-030	September 28, 2022	October 29, 2022	U24
NCI Clinical and Translational Exploratory/Developmental Studies (Clinical Trial Optional)	PAR-22-216	September 10, 2022	July 2, 2025	R21
Precision Approaches in Radiation Synthetic Combinations (PAIRS) (Clinical Trials Optional)	PAR-22-198 PAR-22-199	September 5, 2022 September 16, 2022	September 8, 2025 September 8, 2025	R01 R21
FOA Highlight The “Precision Approaches in Radiation Synthetic Combinations (PAIRS)” program seeks to support collaborative R21 and R01 (clinical trial optional) research projects that leverage the conditional effects of radiation treatment working in tandem with molecularly targeted agents to either generate or greatly enhance actionable vulnerabilities in cancer. The goal is to develop and test new radiation-synthetic combination strategies and facilitate their adoption into the precision medicine toolkit toward building new and effective anticancer treatments.
Limited Competition: Cancer Immune Monitoring and Analysis Centers (CIMACs) and Cancer Immunologic Data Center (CIDC) (Clinical Trial Not Allowed)	RFA-CA-22-038	September 24, 2022	October 25, 2022	U24

Due September 23, 2022 — Applications for the Administrative Supplements to Support Cancer Disparity Collaborative Research Program

This program seeks to catalyze and broaden research and collaborations across the Cancer Health Disparities (CHD) spectrum by:

• supporting new CHD research among investigators who do not normally conduct it
• encouraging the partnership of experienced cancer research investigators with CHD-focused researchers.
• aiming to accelerate and strengthen multi-disciplinary CHD research in wide-ranging areas.

The Collaborative webpage provides important information on this funding opportunity, including a fact sheet, frequently asked questions, program contact information, and pre-application webinar recording and slides.