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Archive for the ‘Cancer – General’ Category

Cancer Policy Related News from Washington DC and New NCI Appointments

Reportor: Stephen J. Williams, PhD.

Biden to announce appointees to Cancer Panel, part of initiative to cut death rate

The president first launched the initiative in 2016 as vice president.

By Mary Kekatos

July 13, 2022, 3:00 PM

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America This Morning

America This Morning

President Joe Biden will announce Wednesday his appointees to the President’s Cancer Panel, ABC News can exclusively reveal.

The Cancer Panel is part of Biden’s Cancer Moonshot Initiative, which was relaunched in February, with a goal of slashing the national cancer death rate by 50% over the next 25 years.MORE: Biden relaunches cancer ‘moonshot’ initiative to help cut death rate

Biden will appoint Dr. Elizabeth Jaffee, Dr. Mitchel Berger and Dr. Carol Brown to the panel, which will advise him and the White House on how to use resources of the federal government to advance cancer research and reduce the burden of cancer in the United States.

Jaffee, who will serve as chair of the panel, is an expert in cancer immunology and pancreatic cancer, according to the White House. She is currently the deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University and previously led the American Association for Cancer Research.

PHOTO: In this Sept. 8, 2016, file photo, Dr. Elizabeth M. Jaffee of the Pancreatic Dream Team attends Stand Up To Cancer (SU2C), a program of the Entertainment Industry Foundation (EIF), in Hollywood, Calif.
In this Sept. 8, 2016, file photo, Dr. Elizabeth M. Jaffee of the Pancreatic Dream Team attends Stand Up To Cancer (SU2C), a program of the Entertainment Industry Foundation (EIF), in Hollywood, Calif.ABC Handout via Getty Images, FILE

Berger, a neurological surgeon, directs the University of California, San Francisco Brain Tumor Center and previously spent 23 years at the school as a professor of neurological surgery.

Brown, a gynecologic oncologist, is the senior vice president and chief health equity officer at Memorial Sloan Kettering Cancer Center in New York City. According to the White House, much of her career has been focused on eliminating cancer care disparities due to racial, ethnic, cultural or socioeconomic factors.

Additionally, First Lady Jill Biden, members of the Cabinet and other administration officials are holding a meeting Wednesday of the Cancer Cabinet, made up of officials across several governmental departments and agencies, the White House said.

The Cabinet will introduce new members and discuss priorities in the battle against cancer including closing the screening gap, addressing potential environmental exposures, reducing the number of preventable cancer and expanding access to cancer research.MORE: Long Island school district found to have higher rates of cancer cases: Study

It is the second meeting of the cabinet since Biden relaunched the initiative in February, which he originally began in 2016 when he was vice president.

Both Jaffee and Berger were members of the Blue Ribbon Panel for the Cancer Moonshot Initiative led by Biden.

The initiative has personal meaning for Biden, whose son, Beau, died of glioblastoma — one of the most aggressive forms of brain cancer — in 2015.

“I committed to this fight when I was vice president,” Biden said at the time, during an event at the White House announcing the relaunch. “It’s one of the reasons why, quite frankly, I ran for president. Let there be no doubt, now that I am president, this is a presidential, White House priority. Period.”

The initiative has several priority actions including diagnosing cancer sooner; preventing cancer; addressing inequities; and supporting patients, caregivers and survivors.

PHOTO: In this June 14, 2016, file photo, Dr. Carol Brown, physician at Memorial Sloan Kettering Cancer Center, gives a presentation, at The White House Summit on The United State of Women, in Washington, D.C.
In this June 14, 2016, file photo, Dr. Carol Brown, physician at Memorial Sloan Kettering Cancer Center, gives a presentation, at The White House Summit on The United State of Women, in Washington, D.C.NurPhoto via Getty Images, FILE

The White House has also issued a call to action to get cancer screenings back to pre-pandemic levels.

More than 9.5 million cancer screenings that would have taken place in 2020 were missed due to the COVID-19 pandemic, according to the National Institutes of Health.MORE: Louisiana’s ‘Cancer Alley’ residents in clean air fight

“We have to get cancer screenings back on track and make sure they’re accessible to all Americans,” Biden said at the time.

Since the first meeting of the Cancer Cabinet, the Centers for Disease Control and Prevention has issued more than $200 million in grants to cancer prevention programs, the Centers for Medicaid & Medicare Services implemented a new model to reduce the cost of cancer care, and the U.S. Patent and Trademark Office said it will fast-track applications for cancer immunotherapies.

ABC News’ Sasha Pezenik contributed to this report.

Biden to tap prominent Harvard cancer surgeon to head National Cancer Institute

Monica Bertagnolli brings leadership experience in cancer clinical trials funded by the $7 billion research agency

headshot of Monica Bertagnolli
Monica BertagnolliASCO; GLENN DAVENPORT

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President Joe Biden is expected to pick cancer surgeon Monica Bertagnolli as the next director of the National Cancer Institute (NCI). Bertagnolli, a physician-scientist at Brigham and Women’s Hospital, the Dana-Farber Cancer Center, and Harvard Medical School, specializes in gastrointestinal cancers and is well known for her expertise in clinical trials. She will replace Ned Sharpless, who stepped down as NCI director in April after nearly 5 years.

The White House has not yet announced the selection, first reported by STAT, but several cancer research organizations closely watching for the nomination have issued statements supporting Bertagnolli’s expected selection. She is “a national leader” in clinical cancer research and “a great person to take the job,” Sharpless told ScienceInsider.

With a budget of $7 billion, NCI is the largest component of the National Institutes of Health (NIH) and the world’s largest funder of cancer research. Its director is the only NIH institute director selected by the president. Bertagnolli’s expected appointment, which does not require Senate confirmation, drew applause from the cancer research community

Margaret Foti, CEO of the American Association for Cancer Research, praised Bertagnolli’s “appreciation for … basic research” and “commitment to ensuring that such treatment innovations reach patients … across the United States.” Ellen Sigal, chair and founder of Friends of Cancer Research, says Bertagnolli “brings expertise the agency needs at a true inflection point for cancer research.”

Bertagnolli, 63, will be the first woman to lead NCI. Her lab research on tumor immunology and the role of a gene called APC in colorectal cancer led to a landmark trial she headed showing that an anti-inflammatory drug can help prevent this cancer. In 2007, she became the chief of surgery at the Dana-Farber Brigham Cancer Center.

She served as president of the American Society of Clinical Oncology in 2018 and currently chairs the Alliance for Clinical Trials in Oncology, which is funded by NCI’s National Clinical Trials Network. The network is a “complicated” program, and “Monica will have a lot of good ideas on how to make it work better,” Sharpless says.

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One of Bertagnolli’s first tasks will be to shape NCI’s role in Biden’s reignited Cancer Moonshot, which aims to slash the U.S. cancer death rate in half within 25 years. NCI’s new leader also needs to sort out how the agency will mesh with a new NIH component that will fund high-risk, goal-driven research, the Advanced Research Projects Agency for Health (ARPA-H).

Bertagnolli will also head NCI efforts already underway to boost grant funding rates, diversify the cancer research workplace, and reduce higher death rates for Black people with cancer.

The White House recently nominated applied physicist Arati Prabhakar to fill another high-level science position, director of the White House Office of Science and Technology Policy (OSTP). But still vacant is the NIH director slot, which Francis Collins, acting science adviser to the president, left in December 2021. And the administration hasn’t yet selected the inaugural director of ARPA-H.

Correction, 22 July, 9 a.m.: This story has been updated to reflect that Francis Collins is acting science adviser to the president, not acting director of the White House Office of Science and Technology Policy.

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Accelerating PROTAC drug discovery: Establishing a relationship between ubiquitination and target protein degradation

Curator: Stephen J. Williams, Ph.D.

PROTACs have been explored in multiple disease fields with focus on only few ligases like cereblon (CRBN), Von Hippel-Lindau (VHL), IAP and MDM2. Cancer targets like androgen receptor, estrogen receptor, BTK, BCL2, CDK8 and c-MET [[6], [7], [8], [9], [10], [11]] have been successfully targeted using PROTACs. A variety of BET family (BRD2, BRD3, and BRD4)- PROTACs were designed using multiple ligases; MDM2-based BRD4 PROTAC [12], CRBN based dBET1 [13] and BETd-24-6 [14] for triple-negative breast cancer, enhanced membrane permeable dBET6 [15], and dBET57 PROTAC [16]. PROTACs for Hepatitis c virus (HCV) protease, IRAK4 and Tau [[17], [18], [19]] have been explored for viral, immune and neurodegenerative diseases, respectively. Currently, the PROTAC field expansion to vast undruggable proteome is hindered due to narrow focus on select E3 ligases. Lack of reliable tools to rapidly evaluate PROTACs based on new ligases is hindering the progress. Screening platforms designed must be physiologically relevant and represent true PROTAC cellular function, i.e., PROTAC-mediated target ubiquitination and degradation.

In the current study, we employ TUBEs as affinity capture reagents to monitor PROTAC-induced poly-ubiquitination and degradation as a measure of potency. We established and validated proof-of-concept cell-based assays in a 96-well format using PROTACS for three therapeutic targets BET family proteins, kinases, and KRAS. To our knowledge, the proposed PROTAC assays are first of its kind that can simultaneously 1) detect ubiquitination of endogenous, native protein targets, 2) evaluate the potency of PROTACs, and 3) establish a link between the UPS and protein degradation. Using these TUBE assays, we established rank order potencies between four BET family PROTACs dBET1, dBET6, BETd246 and dBET57 based on peak ubiquitination signals (“UbMax”) of the target protein. TUBE assay was successful in demonstrating promiscuous kinase PROTACs efficiency to degrade Aurora Kinase A at sub-nanomolar concentrations within 1 h. A comparative study to identify changes in the ubiquitination and degradation profile of KRAS G12C PROTACs recruiting two E3 ligases (CRBN and VHL). All of the ubiquitination and degradation profiles obtained from TUBE based assays correlate well with traditional low throughput immunoblotting. Significant correlation between DC50 obtained from protein degradation in western blotting and UbMax values demonstrates our proposed assays can aid in high-throughput screening and drastically eliminate artifacts to overcome bottlenecks in PROTAC drug discovery.

To successfully set up HTS screening with novel PROTACs without pre-existing knowledge, we recommend the following steps. 1. Identify a model PROTAC that can potentially demonstrate activity based on knowledge in PROTAC design or in vitro binding studies. 2. Perform a time course study with 2–3 doses of the model PROTAC based on affinities of the ligands selected. 3. Monitor ubiquitination and degradation profiles using plate-based assay and identify time point that demonstrates UbMax. 4. Perform a dose response at selected time point with a library of PROTACs to establish rank order potency.

INTRODUCTION

Ubiquitination is a major regulatory mechanism to maintain cellular protein homeostasis by marking proteins for proteasomal-mediated degradation [1]. Given ubiquitin’s role in a variety of pathologies, the idea of targeting the Ubiquitin Proteasome System (UPS) is at the forefront of drug discovery [2]. “Event-driven” protein degradation using the cell’s own UPS is a promising technology for addressing the “undruggable” proteome [3]. Targeted protein degradation (TPD) has emerged as a new paradigm and promising therapeutic option to selectively attack previously intractable drug targets using PROteolytic TArgeting Chimeras (PROTACs) [4]. PROTACs are heterobifunctional molecules with a distinct ligand that targets a specific E3 ligase which is tethered to another ligand specific for the target protein using an optimized chemical linker. A functional PROTAC induces a ternary E3-PROTAC-target complex, resulting in poly-ubiquitination and subsequent controlled protein degradation [5]. Ability to function at sub-stoichiometric levels for efficient degradation, a significant advantage over traditional small molecules.

PROTACs have been explored in multiple disease fields with focus on only few ligases like cereblon (CRBN), Von Hippel-Lindau (VHL), IAP and MDM2. Cancer targets like androgen receptorestrogen receptor, BTK, BCL2, CDK8 and c-MET [[6][7][8][9][10][11]] have been successfully targeted using PROTACs. A variety of BET family (BRD2, BRD3, and BRD4)- PROTACs were designed using multiple ligases; MDM2-based BRD4 PROTAC [12], CRBN based dBET1 [13] and BETd-24-6 [14] for triple-negative breast cancer, enhanced membrane permeable dBET6 [15], and dBET57 PROTAC [16]. PROTACs for Hepatitis c virus (HCV) proteaseIRAK4 and Tau [[17][18][19]] have been explored for viral, immune and neurodegenerative diseases, respectively. Currently, the PROTAC field expansion to vast undruggable proteome is hindered due to narrow focus on select E3 ligases. Lack of reliable tools to rapidly evaluate PROTACs based on new ligases is hindering the progress. Screening platforms designed must be physiologically relevant and represent true PROTAC cellular function, i.e., PROTAC-mediated target ubiquitination and degradation.

Cellular PROTAC screening is traditionally performed using cell lines harboring reporter genes and/or Western blotting. While Western blotting is easy to perform, they are low throughput, semi-quantitative and lack sensitivity. While reporter gene assays address some of the issues, they are challenged by reporter tags having internal lysines leading to artifacts. Currently, no approaches are available that can identify true PROTAC effects such as target ubiquitination and proteasome-mediated degradation simultaneously. High affinity ubiquitin capture reagents like TUBEs [20] (tandem ubiquitin binding entities), are engineered ubiquitin binding domains (UBDs) that allow for detection of ultralow levels of polyubiquitinated proteins under native conditions with affinities as low as 1 nM. The versatility and selectivity of TUBEs makes them superior to antibodies, and they also offer chain-selectivity (-K48, -K63, or linear) [21]. High throughput assays that can report the efficacy of multiple PROTACs simultaneously by monitoring PROTAC mediated ubiquitination can help establish rank order potency and guide chemists in developing meaningful structure activity relationships (SAR) rapidly.

In the current study, we employ TUBEs as affinity capture reagents to monitor PROTAC-induced poly-ubiquitination and degradation as a measure of potency. We established and validated proof-of-concept cell-based assays in a 96-well format using PROTACS for three therapeutic targets BET family proteins, kinases, and KRAS. To our knowledge, the proposed PROTAC assays are first of its kind that can simultaneously 1) detect ubiquitination of endogenous, native protein targets, 2) evaluate the potency of PROTACs, and 3) establish a link between the UPS and protein degradation. Using these TUBE assays, we established rank order potencies between four BET family PROTACs dBET1, dBET6, BETd246 and dBET57 based on peak ubiquitination signals (“UbMax”) of the target protein. TUBE assay was successful in demonstrating promiscuous kinase PROTACs efficiency to degrade Aurora Kinase A at sub-nanomolar concentrations within 1 h. A comparative study to identify changes in the ubiquitination and degradation profile of KRAS G12C PROTACs recruiting two E3 ligases (CRBN and VHL). All of the ubiquitination and degradation profiles obtained from TUBE based assays correlate well with traditional low throughput immunoblotting. Significant correlation between DC50 obtained from protein degradation in western blotting and UbMax values demonstrates our proposed assays can aid in high-throughput screening and drastically eliminate artifacts to overcome bottlenecks in PROTAC drug discovery.

Fig. 1. Schematic representation of TUBE assay to monitor PROTAC mediated cellular ubiquitination of target proteins.
Fig. 2. TUBE based assay screening of PROTACs: Jurkat cell lysates were treated with BRD3-specific PROTACs A) dBET1, B) dBET6, C) BETd24-6, and D) dBET57. Polyubiquitination profiles and Ubmax of BRD3 for each PROTAC were represented as relative CL intensity. Relative CL intensities were calculated by dividing raw CL signals from a given PROTAC dose over DMSO treated samples. Error bars represent standard deviations, n = 3.
Fig. 3. PROTAC mediated degradation of bromodomain proteins analyzed by anti-BRD3 western blotting. Dose response of PROTACs dBET1, dBET6, Betd-24-6 and dBET57 at 45 min in Jurkat cells demonstrates degradation of BRD3, Acting as loading control.

 

 

 

 

 

 

 

 

 

Fig. 4. PROTAC mediated ubiquitination and degradation of AURKA in K562 cells. (A) Time course study to evaluate intracellular ubiquitination and degradation. (B) Western blot analysis of time course study: degradation kinetics (C) A dose response study to evaluate DC50 of the promiscuous kinase PROTAC in K562 cells. (D) Western blot analysis of dose response study to monitor degradation, GAPDH as loading control. Error bars represent standard deviation, n = 3.

SOURCE

https://www.sciencedirect.com/science/article/abs/pii/S0006291X22011792

Other articles of PROTACs in this Open Access Journal Include

The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

The Map of human proteins drawn by artificial intelligence and PROTAC (proteolysis targeting chimeras) Technology for Drug Discovery

Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Late Day Sessions

From High-Throughput Assay to Systems Biology: New Tools for Drug Discovery

 

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New studies link cell cycle proteins to immunosurveillance of premalignant cells

Curator: Stephen J. Williams, Ph.D.

The following is from a Perspectives article in the journal Science by Virinder Reen and Jesus Gil called “Clearing Stressed Cells: Cell cycle arrest produces a p21-dependent secretome that initaites immunosurveillance of premalignant cells”. This is a synopsis of the Sturmlechener et al. research article in the same issue (2).

Complex organisms repair stress-induced damage to limit the replication of faulty cells that could drive cancer. When repair is not possible, tissue homeostasis is maintained by the activation of stress response programs such as apoptosis, which eliminates the cells, or senescence, which arrests them (1). Cellular senescence causes the arrest of damaged cells through the induction of cyclin-dependent kinase inhibitors (CDKIs) such as p16 and p21 (2). Senescent cells also produce a bioactive secretome (the senescence-associated secretory phenotype, SASP) that places cells under immunosurveillance, which is key to avoiding the detrimental inflammatory effects caused by lingering senescent cells on surrounding tissues. On page 577 of this issue, Sturmlechner et al. (3) report that induction of p21 not only contributes to the arrest of senescent cells, but is also an early signal that primes stressed cells for immunosurveillance.Senescence is a complex program that is tightly regulated at the epigenetic and transcriptional levels. For example, exit from the cell cycle is controlled by the induction of p16 and p21, which inhibit phosphorylation of the retinoblastoma protein (RB), a transcriptional regulator and tumor suppressor. Hypophosphorylated RB represses transcription of E2F target genes, which are necessary for cell cycle progression. Conversely, production of the SASP is regulated by a complex program that involves super-enhancer (SE) remodeling and activation of transcriptional regulators such as nuclear factor κB (NF-κB) or CCAAT enhancer binding protein–β (C/EBPβ) (4).

Senescence is a complex program that is tightly regulated at the epigenetic and transcriptional levels. For example, exit from the cell cycle is controlled by the induction of p16 and p21, which inhibit phosphorylation of the retinoblastoma protein (RB), a transcriptional regulator and tumor suppressor. Hypophosphorylated RB represses transcription of E2F target genes, which are necessary for cell cycle progression. Conversely, production of the SASP is regulated by a complex program that involves super-enhancer (SE) remodeling and activation of transcriptional regulators such as nuclear factor κB (NF-κB) or CCAAT enhancer binding protein–β (C/EBPβ) (4).

Sturmlechner et al. found that activation of p21 following stress rapidly halted cell cycle progression and triggered an internal biological timer (of ∼4 days in hepatocytes), allowing time to repair and resolve damage (see the figure). In parallel, C-X-C motif chemokine 14 (CXCL14), a component of the PASP, attracted macrophages to surround and closely surveil these damaged cells. Stressed cells that recovered and normalized p21 expression suspended PASP production and circumvented immunosurveillance. However, if the p21-induced stress was unmanageable, the repair timer expired, and the immune cells transitioned from surveillance to clearance mode. Adjacent macrophages mounted a cytotoxic T lymphocyte response that destroyed damaged cells. Notably, the overexpression of p21 alone was sufficient to orchestrate immune killing of stressed cells, without the need of a senescence phenotype. Overexpression of other CDKIs, such as p16 and p27, did not trigger immunosurveillance, likely because they do not induce CXCL14 expression.In the context of cancer, senescent cell clearance was first observed following reactivation of the tumor suppressor p53 in liver cancer cells. Restoring p53 signaling induced senescence and triggered the elimination of senescent cells by the innate immune system, prompting tumor regression (5). Subsequent work has revealed that the SASP alerts the immune system to target preneoplastic senescent cells. Hepatocytes expressing the oncogenic mutant NRASG12V (Gly12→Val) become senescent and secrete chemokines and cytokines that trigger CD4+ T cell–mediated clearance (6). Despite the relevance for tumor suppression, relatively little is known about how immunosurveillance of oncogene-induced senescent cells is initiated and controlled.

Source of image: Reen, V. and Gil, J. Clearing Stressed Cells. Science Perspectives 2021;Vol 374(6567) p 534-535.

References

2. Sturmlechner I, Zhang C, Sine CC, van Deursen EJ, Jeganathan KB, Hamada N, Grasic J, Friedman D, Stutchman JT, Can I, Hamada M, Lim DY, Lee JH, Ordog T, Laberge RM, Shapiro V, Baker DJ, Li H, van Deursen JM. p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science. 2021 Oct 29;374(6567):eabb3420. doi: 10.1126/science.abb3420. Epub 2021 Oct 29. PMID: 34709885.

More Articles on Cancer, Senescence and the Immune System in this Open Access Online Scientific Journal Include

Bispecific and Trispecific Engagers: NK-T Cells and Cancer Therapy

Natural Killer Cell Response: Treatment of Cancer

Issues Need to be Resolved With ImmunoModulatory Therapies: NK cells, mAbs, and adoptive T cells

New insights in cancer, cancer immunogenesis and circulating cancer cells

Insight on Cell Senescence

Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

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NCCN Shares Latest Expert Recommendations for Prostate Cancer in Spanish and Portuguese

Reporter: Stephen J. Williams, Ph.D.

Currently many biomedical texts and US government agency guidelines are only offered in English or only offered in different languages upon request. However Spanish is spoken in a majority of countries worldwide and medical text in that language would serve as an under-served need. In addition, Portuguese is the main language in the largest country in South America, Brazil.

The LPBI Group and others have noticed this need for medical translation to other languages. Currently LPBI Group is translating their medical e-book offerings into Spanish (for more details see https://pharmaceuticalintelligence.com/vision/)

Below is an article on The National Comprehensive Cancer Network’s decision to offer their cancer treatment guidelines in Spanish and Portuguese.

Source: https://www.nccn.org/home/news/newsdetails?NewsId=2871

PLYMOUTH MEETING, PA [8 September, 2021] — The National Comprehensive Cancer Network® (NCCN®)—a nonprofit alliance of leading cancer centers in the United States—announces recently-updated versions of evidence- and expert consensus-based guidelines for treating prostate cancer, translated into Spanish and Portuguese. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) feature frequently updated cancer treatment recommendations from multidisciplinary panels of experts across NCCN Member Institutions. Independent studies have repeatedly found that following these recommendations correlates with better outcomes and longer survival.

“Everyone with prostate cancer should have access to care that is based on current and reliable evidence,” said Robert W. Carlson, MD, Chief Executive Officer, NCCN. “These updated translations—along with all of our other translated and adapted resources—help us to define and advance high-quality, high-value, patient-centered cancer care globally, so patients everywhere can live better lives.”

Prostate cancer is the second most commonly occurring cancer in men, impacting more than a million people worldwide every year.[1] In 2020, the NCCN Guidelines® for Prostate Cancer were downloaded more than 200,000 times by people outside of the United States. Approximately 47 percent of registered users for NCCN.org are located outside the U.S., with Brazil, Spain, and Mexico among the top ten countries represented.

“NCCN Guidelines are incredibly helpful resources in the work we do to ensure cancer care across Latin America meets the highest standards,” said Diogo Bastos, MD, and Andrey Soares, MD, Chair and Scientific Director of the Genitourinary Group of The Latin American Cooperative Oncology Group (LACOG). The organization has worked with NCCN in the past to develop Latin American editions of the NCCN Guidelines for Breast Cancer, Colon Cancer, Non-Small Cell Lung Cancer, Prostate Cancer, Multiple Myeloma, and Rectal Cancer, and co-hosted a webinar on “Management of Prostate Cancer for Latin America” earlier this year. “We appreciate all of NCCN’s efforts to make sure these gold-standard recommendations are accessible to non-English speakers and applicable for varying circumstances.”

NCCN also publishes NCCN Guidelines for Patients®, containing the same treatment information in non-medical terms, intended for patients and caregivers. The NCCN Guidelines for Patients: Prostate Cancer were found to be among the most trustworthy sources of information online according to a recent international study. These patient guidelines have been divided into two books, covering early and advanced prostate cancer; both have been translated into Spanish and Portuguese as well.

NCCN collaborates with organizations across the globe on resources based on the NCCN Guidelines that account for local accessibility, consideration of metabolic differences in populations, and regional regulatory variation. They can be downloaded free-of-charge for non-commercial use at NCCN.org/global or via the Virtual Library of NCCN Guidelines App. Learn more and join the conversation with the hashtag #NCCNGlobal.


[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, in press. The online GLOBOCAN 2018 database is accessible at http://gco.iarc.fr/, as part of IARC’s Global Cancer Observatory.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, efficient, and accessible cancer care so patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) provide transparent, evidence-based, expert consensus recommendations for cancer treatment, prevention, and supportive services; they are the recognized standard for clinical direction and policy in cancer management and the most thorough and frequently-updated clinical practice guidelines available in any area of medicine. The NCCN Guidelines for Patients® provide expert cancer treatment information to inform and empower patients and caregivers, through support from the NCCN Foundation®. NCCN also advances continuing educationglobal initiativespolicy, and research collaboration and publication in oncology. Visit NCCN.org for more information and follow NCCN on Facebook @NCCNorg, Instagram @NCCNorg, and Twitter @NCCN.

Please see LPBI Group’s efforts in medical text translation and Natural Language Processing of Medical Text at

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Reporter: Danielle Smolyar, Research Assistant 3 – Text Analysis for 2.0 LPBI Group’s TNS #1 – 2020/2021 Academic Internship in Medical Text Analysis (MTA)

Image source by https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html
 
Credit: Pixabay/CC0 Public Domain 

Recently, researchers at Mount Sinai were able to develop a therapeutic agent that shows high levels of effectiveness in Vitro disrupting a biological pathway that allow cancer to survive. This finding is according to a paper which was published in Cancer Discovery, which is a Journal of the American Association of cancer research in July 2021.

The therapy in which they focus on is a molecule named MS21, which causes the degradation of AKT which is an enzyme that is very active and present in cancers. In this study there was much evidence that pharmacological degradation of AKT is a feasible treatment for cancer’s which have a mutation in certain genes. 

AKT is a cancer gene that encodes an enzyme that is abnormally activated in cancer cells to stimulate tumor growth. The degradation of AKT reverses all these processes which ultimately inhibits further tumor growth.

“Our study lays a solid foundation for the clinical development of an AKT degrader for the treatment of human cancers with certain gene mutations,” said Ramon Parsons, MD, Ph.D., Director of The Tisch Cancer Institute and Ward-Coleman Chair in Cancer Research and Chair of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. “Examination of 44,000 human cancers identified that 19 percent of tumors have at least one of these mutations, suggesting that a large population of cancer patients could benefit from therapy with an AKT degrader such as MS21.”

https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html.

MS21 was tested and human cancer derived cell lines, is used in Laboratories as a model to study the efficacy of different cancer therapies.

At Mount Sinai they were looking to develop MS21 with an industry partner in order to open clinical trials for patients. 

“Translating these findings into effective cancer therapies for patients is a high priority because the mutations and the resulting cancer-driving pathways that we lay out in this study are arguably the most commonly activated pathways in human cancer, but this effort has proven to be particularly challenging,” said Jian Jin, Ph.D., Mount Sinai Professor in Therapeutics Discovery and Director of the Mount Sinai Center for Therapeutics Discovery at Icahn Mount Sinai. “We look forward to an opportunity to develop this molecule into a therapy that is ready to be studied in clinical trials.”

https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html.

Image credit: National Cancer Institute

Original article: 

Researchers develop novel therapy that could be effective in many cancers

staff, S. X. (2021, July 23). R. Medical Xpress – by The Mount Sinai Hospital

https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html. 

Other related articles published on this Open Access Online Scientific Journal include the following:

Machine Learning (ML) in cancer prognosis prediction helps the researcher to identify multiple known as well as candidate cancer diver genes

Reporter and Curator: Dr. Pati

https://pharmaceuticalintelligence.com/2021/05/04/machine-learning-ml-in-cancer-prognosis-prediction-helps-the-researcher-to-identify-multiple-known-as-well-as-candidate-cancer-diver-genes/

New approaches to cancer therapy using mathematics

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2021/02/12/new-approaches-to-cancer-therapy-using-mathematics/

Cancer treatment using CRISPR-based Genome Editing System

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2021/01/09/59906/

Novel biomarkers for targeting cancer immunotherapy

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/10/10/novel-biomarkers-for-targeting-cancer-immunotherapy/

Novel Approaches to Cancer Therapy [11.1]


Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/04/11/novel-approaches-to-cancer-therapy-7-12/

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From High-Throughput Assay to Systems Biology: New Tools for Drug Discovery

Curator: Stephen J. Williams, PhD

Marc W. Kirschner*

Department of Systems Biology
Harvard Medical School

Boston, Massachusetts 02115

With the new excitement about systems biology, there is understandable interest in a definition. This has proven somewhat difficult. Scientific fields, like spe­cies, arise by descent with modification, so in their ear­liest forms even the founders of great dynasties are only marginally different than their sister fields and spe­cies. It is only in retrospect that we can recognize the significant founding events. Before embarking on a def­inition of systems biology, it may be worth remember­ing that confusion and controversy surrounded the in­troduction of the term “molecular biology,” with claims that it hardly differed from biochemistry. Yet in retro­spect molecular biology was new and different. It intro­duced both new subject matter and new technological approaches, in addition to a new style.

As a point of departure for systems biology, consider the quintessential experiment in the founding of molec­ular biology, the one gene one enzyme hypothesis of Beadle and Tatum. This experiment first connected the genotype directly to the phenotype on a molecular level, although efforts in that direction can certainly be found in the work of Archibald Garrod, Sewell Wright, and others. Here a protein (in this case an enzyme) is seen to be a product of a single gene, and a single function; the completion of a specific step in amino acid biosynthesis is the direct result. It took the next 30 years to fill in the gaps in this process. Yet the one gene one enzyme hypothesis looks very different to us today. What is the function of tubulin, of PI-3 kinase or of rac? Could we accurately predict the phenotype of a nonle­thal mutation in these genes in a multicellular organ­ism? Although we can connect structure to the gene, we can no longer infer its larger purpose in the cell or in the organism. There are too many purposes; what the protein does is defined by context. The context also includes a history, either developmental or physiologi­cal. Thus the behavior of the Wnt signaling pathway depends on the previous lineage, the “where and when” questions of embryonic development. Similarly the behavior of the immune system depends on previ­ous experience in a variable environment. All of these features stress how inadequate an explanation for function we can achieve solely by trying to identify genes (by annotating them!) and characterizing their transcriptional control circuits.

That we are at a crossroads in how to explore biology is not at all clear to many. Biology is hardly in its dotage; the process of discovery seems to have been per­fected, accelerated, and made universally applicable to all fields of biology. With the completion of the human genome and the genomes of other species, we have a glimpse of many more genes than we ever had before to study. We are like naturalists discovering a new con­tinent, enthralled with the diversity itself. But we have also at the same time glimpsed the finiteness of this list of genes, a disturbingly small list. We have seen that the diversity of genes cannot approximate the diversity of functions within an organism. In response, we have argued that combinatorial use of small numbers of components can generate all the diversity that is needed. This has had its recent incarnation in the sim­plistic view that the rules of cis-regulatory control on DNA can directly lead to an understanding of organ­isms and their evolution. Yet this assumes that the gene products can be linked together in arbitrary combina­tions, something that is not assured in chemistry. It also downplays the significant regulatory features that in­volve interactions between gene products, their local­ization, binding, posttranslational modification, degra­dation, etc. The big question to understand in biology is not regulatory linkage but the nature of biological systems that allows them to be linked together in many nonlethal and even useful combinations. More and more we come to realize that understanding the con­served genes and their conserved circuits will require an understanding of their special properties that allow them to function together to generate different pheno­types in different tissues of metazoan organisms. These circuits may have certain robustness, but more impor­tant they have adaptability and versatility. The ease of putting conserved processes under regulatory control is an inherent design feature of the processes them­selves. Among other things it loads the deck in evolu­tionary variation and makes it more feasible to generate useful phenotypes upon which selection can act.

Systems biology offers an opportunity to study how the phenotype is generated from the genotype and with it a glimpse of how evolution has crafted the pheno­type. One aspect of systems biology is the develop­ment of techniques to examine broadly the level of pro­tein, RNA, and DNA on a gene by gene basis and even the posttranslational modification and localization of proteins. In a very short time we have witnessed the development of high-throughput biology, forcing us to consider cellular processes in toto. Even though much of the data is noisy and today partially inconsistent and incomplete, this has been a radical shift in the way we tear apart problems one interaction at a time. When coupled with gene deletions by RNAi and classical methods, and with the use of chemical tools tailored to proteins and protein domains, these high-throughput techniques become still more powerful.

High-throughput biology has opened up another im­portant area of systems biology: it has brought us out into the field again or at least made us aware that there is a world outside our laboratories. Our model systems have been chosen intentionally to be of limited genetic diversity and examined in a highly controlled and repro­ducible environment. The real world of ecology, evolu­tion, and human disease is a very different place. When genetics separated from the rest of biology in the early part of the 20th century, most geneticists sought to understand heredity and chose to study traits in the organism that could be easily scored and could be used to reveal genetic mechanisms. This was later ex­tended to powerful effect to use genetics to study cell biological and developmental mechanisms. Some ge­neticists, including a large school in Russia in the early 20th century, continued to study the genetics of natural populations, focusing on traits important for survival. That branch of genetics is coming back strongly with the power of phenotypic assays on the RNA and pro­tein level. As human beings we are most concerned not with using our genetic misfortunes to unravel biology’s complexity (important as that is) but with the role of our genetics in our individual survival. The context for understanding this is still not available, even though the data are now coming in torrents, for many of the genes that will contribute to our survival will have small quan­titative effects, partially masked or accentuated by other genetic and environmental conditions. To under­stand the genetic basis of disease will require not just mapping these genes but an understanding of how the phenotype is created in the first place and the messy interactions between genetic variation and environ­mental variation.

Extracts and explants are relatively accessible to syn­thetic manipulation. Next there is the explicit recon­struction of circuits within cells or the deliberate modifi­cation of those circuits. This has occurred for a while in biology, but the difference is that now we wish to construct or intervene with the explicit purpose of de­scribing the dynamical features of these synthetic or partially synthetic systems. There are more and more tools to intervene and more and more tools to measure. Although these fall short of total descriptions of cells and organisms, the detailed information will give us a sense of the special life-like processes of circuits, pro­teins, cells in tissues, and whole organisms in their en­vironment. This meso-scale systems biology will help establish the correspondence between molecules and large-scale physiology.

You are probably running out of patience for some definition of systems biology. In any case, I do not think the explicit definition of systems biology should come from me but should await the words of the first great modern systems biologist. She or he is probably among us now. However, if forced to provide some kind of label for systems biology, I would simply say that systems biology is the study of the behavior of complex biologi­cal organization and processes in terms of the molecu­lar constituents. It is built on molecular biology in its special concern for information transfer, on physiology for its special concern with adaptive states of the cell and organism, on developmental biology for the impor­tance of defining a succession of physiological states in that process, and on evolutionary biology and ecol­ogy for the appreciation that all aspects of the organ­ism are products of selection, a selection we rarely understand on a molecular level. Systems biology attempts all of this through quantitative measurement, modeling, reconstruction, and theory. Systems biology is not a branch of physics but differs from physics in that the primary task is to understand how biology gen­erates variation. No such imperative to create variation exists in the physical world. It is a new principle that Darwin understood and upon which all of life hinges. That sounds different enough for me to justify a new field and a new name. Furthermore, the success of sys­tems biology is essential if we are to understand life; its success is far from assured—a good field for those seeking risk and adventure.

Source: “Meaning of Systems Biology” Cell, Vol. 121, 503–504, May 20, 2005, DOI 10.1016/j.cell.2005.05.005

Old High-throughput Screening, Once the Gold Standard in Drug Development, Gets a Systems Biology Facelift

From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

Quentin T. L. Pasquer, Ioannis A. Tsakoumagkos and Sascha Hoogendoorn 

Molecules 202025(23), 5702; https://doi.org/10.3390/molecules25235702

Abstract

Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.

5.1.5. Large-Scale Proteomics

While FITExP is based on protein expression regulation during apoptosis, a study of Ruprecht et al. showed that proteomic changes are induced both by cytotoxic and non-cytotoxic compounds, which can be detected by mass spectrometry to give information on a compound’s mechanism of action. They developed a large-scale proteome-wide mass spectrometry analysis platform for MOA studies, profiling five lung cancer cell lines with over 50 drugs. Aggregation analysis over the different cell lines and the different compounds showed that one-quarter of the drugs changed the abundance of their protein target. This approach allowed target confirmation of molecular degraders such as PROTACs or molecular glues. Finally, this method yielded unexpected off-target mechanisms for the MAP2K1/2 inhibitor PD184352 and the ALK inhibitor ceritinib [97]. While such a mapping approach clearly provides a wealth of information, it might not be easily attainable for groups that are not equipped for high-throughput endeavors.

All-in-all, mass spectrometry methods have gained a lot of traction in recent years and have been successfully applied for target deconvolution and MOA studies of small molecules. As with all high-throughput methods, challenges lie in the accessibility of the instruments (both from a time and cost perspective) and data analysis of complex and extensive data sets.

5.2. Genetic Approaches

Both label-based and mass spectrometry proteomic approaches are based on the physical interaction between a small molecule and a protein target, and focus on the proteome for target deconvolution. It has been long realized that genetics provides an alternative avenue to understand a compound’s action, either through precise modification of protein levels, or by inducing protein mutations. First realized in yeast as a genetically tractable organism over 20 years ago, recent advances in genetic manipulation of mammalian cells have opened up important opportunities for target identification and MOA studies through genetic screening in relevant cell types [98]. Genetic approaches can be roughly divided into two main areas, with the first centering on the identification of mutations that confer compound resistance (Figure 3a), and the second on genome-wide perturbation of gene function and the concomitant changes in sensitivity to the compound (Figure 3b). While both methods can be used to identify or confirm drug targets, the latter category often provides many additional insights in the compound’s mode of action.

Figure 3. Genetic methods for target identification and mode of action studies. Schematic representations of (a) resistance cloning, and (b) chemogenetic interaction screens.

5.2.1. Resistance Cloning

The “gold standard” in drug target confirmation is to identify mutations in the presumed target protein that render it insensitive to drug treatment. Conversely, different groups have sought to use this principle as a target identification method based on the concept that cells grown in the presence of a cytotoxic drug will either die or develop mutations that will make them resistant to the compound. With recent advances in deep sequencing it is now possible to then scan the transcriptome [99] or genome [100] of the cells for resistance-inducing mutations. Genes that are mutated are then hypothesized to encode the protein target. For this approach to be successful, there are two initial requirements: (1) the compound needs to be cytotoxic for resistant clones to arise, and (2) the cell line needs to be genetically unstable for mutations to occur in a reasonable timeframe.

In 2012, the Kapoor group demonstrated in a proof-of-concept study that resistance cloning in mammalian cells, coupled to transcriptome sequencing (RNA-seq), yields the known polo-like kinase 1 (PLK1) target of the small molecule BI 2536. For this, they used the cancer cell line HCT-116, which is deficient in mismatch repair and consequently prone to mutations. They generated and sequenced multiple resistant clones, and clustered the clones based on similarity. PLK1 was the only gene that was mutated in multiple groups. Of note, one of the groups did not contain PLK1 mutations, but rather developed resistance through upregulation of ABCBA1, a drug efflux transporter, which is a general and non-specific resistance mechanism [101]. In a following study, they optimized their pipeline “DrugTargetSeqR”, by counter-screening for these types of multidrug resistance mechanisms so that these clones were excluded from further analysis (Figure 3a). Furthermore, they used CRISPR/Cas9-mediated gene editing to determine which mutations were sufficient to confer drug resistance, and as independent validation of the biochemical relevance of the obtained hits [102].

While HCT-116 cells are a useful model cell line for resistance cloning because of their genomic instability, they may not always be the cell line of choice, depending on the compound and process that is studied. Povedana et al. used CRISPR/Cas9 to engineer mismatch repair deficiencies in Ewing sarcoma cells and small cell lung cancer cells. They found that deletion of MSH2 results in hypermutations in these normally mutationally silent cells, resulting in the formation of resistant clones in the presence of bortezomib, MLN4924, and CD437, which are all cytotoxic compounds [103]. Recently, Neggers et al. reasoned that CRISPR/Cas9-induced non-homologous end-joining repair could be a viable strategy to create a wide variety of functional mutants of essential genes through in-frame mutations. Using a tiled sgRNA library targeting 75 target genes of investigational neoplastic drugs in HAP1 and K562 cells, they generated several KPT-9274 (an anticancer agent with unknown target)-resistant clones, and subsequent deep sequencing showed that the resistant clones were enriched in NAMPT sgRNAs. Direct target engagement was confirmed by co-crystallizing the compound with NAMPT [104]. In addition to these genetic mutation strategies, an alternative method is to grow the cells in the presence of a mutagenic chemical to induce higher mutagenesis rates [105,106].

When there is already a hypothesis on the pathway involved in compound action, the resistance cloning methodology can be extended to non-cytotoxic compounds. Sekine et al. developed a fluorescent reporter model for the integrated stress response, and used this cell line for target deconvolution of a small molecule inhibitor towards this pathway (ISRIB). Reporter cells were chemically mutagenized, and ISRIB-resistant clones were isolated by flow cytometry, yielding clones with various mutations in the delta subunit of guanine nucleotide exchange factor eIF2B [107].

While there are certainly successful examples of resistance cloning yielding a compound’s direct target as discussed above, resistance could also be caused by mutations or copy number alterations in downstream components of a signaling pathway. This is illustrated by clinical examples of acquired resistance to small molecules, nature’s way of “resistance cloning”. For example, resistance mechanisms in Hedgehog pathway-driven cancers towards the Smoothened inhibitor vismodegib include compound-resistant mutations in Smoothened, but also copy number changes in downstream activators SUFU and GLI2 [108]. It is, therefore, essential to conduct follow-up studies to confirm a direct interaction between a compound and the hit protein, as well as a lack of interaction with the mutated protein.

5.2.3. “Chemogenomics”: Examples of Gene-Drug Interaction Screens

When genetic perturbations are combined with small molecule drugs in a chemogenetic interaction screen, the effect of a gene’s perturbation on compound action is studied. Gene perturbation can render the cells resistant to the compound (suppressor interaction), or conversely, result in hypersensitivity and enhanced compound potency (synergistic interaction) [5,117,121]. Typically, cells are treated with the compound at a sublethal dose, to ascertain that both types of interactions can be found in the final dataset, and often it is necessary to use a variety of compound doses (i.e., LD20, LD30, LD50) and timepoints to obtain reliable insights (Figure 3b).

An early example of successful coupling of a phenotypic screen and downstream genetic screening for target identification is the study of Matheny et al. They identified STF-118804 as a compound with antileukemic properties. Treatment of MV411 cells, stably transduced with a high complexity, genome-wide shRNA library, with STF-118804 (4 rounds of increasing concentration) or DMSO control resulted in a marked depletion of cells containing shRNAs against nicotinamide phosphoribosyl transferase (NAMPT) [122].

The Bassik lab subsequently directly compared the performance of shRNA-mediated knockdown versus CRISPR/Cas9-knockout screens for the target elucidation of the antiviral drug GSK983. The data coming out of both screens were complementary, with the shRNA screen resulting in hits leading to the direct compound target and the CRISPR screen giving information on cellular mechanisms of action of the compound. A reason for this is likely the level of protein depletion that is reached by these methods: shRNAs lead to decreased protein levels, which is advantageous when studying essential genes. However, knockdown may not result in a phenotype for non-essential genes, in which case a full CRISPR-mediated knockout is necessary to observe effects [123].

Another NAMPT inhibitor was identified in a CRISPR/Cas9 “haplo-insufficiency (HIP)”-like approach [124]. Haploinsuffiency profiling is a well-established system in yeast which is performed in a ~50% protein background by heterozygous deletions [125]. As there is no control over CRISPR-mediated loss of alleles, compound treatment was performed at several timepoints after addition of the sgRNA library to HCT116 cells stably expressing Cas9, in the hope that editing would be incomplete at early timepoints, resulting in residual protein levels. Indeed, NAMPT was found to be the target of phenotypic hit LB-60-OF61, especially at earlier timepoints, confirming the hypothesis that some level of protein needs to be present to identify a compound’s direct target [124]. This approach was confirmed in another study, thereby showing that direct target identification through CRISPR-knockout screens is indeed possible [126].

An alternative strategy was employed by the Weissman lab, where they combined genome-wide CRISPR-interference and -activation screens to identify the target of the phase 3 drug rigosertib. They focused on hits that had opposite action in both screens, as in sensitizing in one but protective in the other, which were related to microtubule stability. In a next step, they created chemical-genetic profiles of a variety of microtubule destabilizing agents, rationalizing that compounds with the same target will have similar drug-gene interactions. For this, they made a focused library of sgRNAs, based on the most high-ranking hits in the rigosertib genome-wide CRISPRi screen, and compared the focused screen results of the different compounds. The profile for rigosertib clustered well with that of ABT-571, and rigorous target validation studies confirmed rigosertib binding to the colchicine binding site of tubulin—the same site as occupied by ABT-571 [127].

From the above examples, it is clear that genetic screens hold a lot of promise for target identification and MOA studies for small molecules. The CRISPR screening field is rapidly evolving, sgRNA libraries are continuously improving and increasingly commercially available, and new tools for data analysis are being developed [128]. The challenge lies in applying these screens to study compounds that are not cytotoxic, where finding the right dosage regimen will not be trivial.

SYSTEMS BIOLOGY AND CANCER RESEARCH & DRUG DISCOVERY

Integrative Analysis of Next-Generation Sequencing for Next-Generation Cancer Research toward Artificial Intelligence

Youngjun Park, Dominik Heider and Anne-Christin Hauschild. Cancers 202113(13), 3148; https://doi.org/10.3390/cancers13133148

Abstract

The rapid improvement of next-generation sequencing (NGS) technologies and their application in large-scale cohorts in cancer research led to common challenges of big data. It opened a new research area incorporating systems biology and machine learning. As large-scale NGS data accumulated, sophisticated data analysis methods became indispensable. In addition, NGS data have been integrated with systems biology to build better predictive models to determine the characteristics of tumors and tumor subtypes. Therefore, various machine learning algorithms were introduced to identify underlying biological mechanisms. In this work, we review novel technologies developed for NGS data analysis, and we describe how these computational methodologies integrate systems biology and omics data. Subsequently, we discuss how deep neural networks outperform other approaches, the potential of graph neural networks (GNN) in systems biology, and the limitations in NGS biomedical research. To reflect on the various challenges and corresponding computational solutions, we will discuss the following three topics: (i) molecular characteristics, (ii) tumor heterogeneity, and (iii) drug discovery. We conclude that machine learning and network-based approaches can add valuable insights and build highly accurate models. However, a well-informed choice of learning algorithm and biological network information is crucial for the success of each specific research question

1. Introduction

The development and widespread use of high-throughput technologies founded the era of big data in biology and medicine. In particular, it led to an accumulation of large-scale data sets that opened a vast amount of possible applications for data-driven methodologies. In cancer, these applications range from fundamental research to clinical applications: molecular characteristics of tumors, tumor heterogeneity, drug discovery and potential treatments strategy. Therefore, data-driven bioinformatics research areas have tailored data mining technologies such as systems biology, machine learning, and deep learning, elaborated in this review paper (see Figure 1 and Figure 2). For example, in systems biology, data-driven approaches are applied to identify vital signaling pathways [1]. This pathway-centric analysis is particularly crucial in cancer research to understand the characteristics and heterogeneity of the tumor and tumor subtypes. Consequently, this high-throughput data-based analysis enables us to explore characteristics of cancers with a systems biology and a systems medicine point of view [2].Combining high-throughput techniques, especially next-generation sequencing (NGS), with appropriate analytical tools has allowed researchers to gain a deeper systematic understanding of cancer at various biological levels, most importantly genomics, transcriptomics, and epigenetics [3,4]. Furthermore, more sophisticated analysis tools based on computational modeling are introduced to decipher underlying molecular mechanisms in various cancer types. The increasing size and complexity of the data required the adaptation of bioinformatics processing pipelines for higher efficiency and sophisticated data mining methodologies, particularly for large-scale, NGS datasets [5]. Nowadays, more and more NGS studies integrate a systems biology approach and combine sequencing data with other types of information, for instance, protein family information, pathway, or protein–protein interaction (PPI) networks, in an integrative analysis. Experimentally validated knowledge in systems biology may enhance analysis models and guides them to uncover novel findings. Such integrated analyses have been useful to extract essential information from high-dimensional NGS data [6,7]. In order to deal with the increasing size and complexity, the application of machine learning, and specifically deep learning methodologies, have become state-of-the-art in NGS data analysis.

Figure 1. Next-generation sequencing data can originate from various experimental and technological conditions. Depending on the purpose of the experiment, one or more of the depicted omics types (Genomics, Transcriptomics, Epigenomics, or Single-Cell Omics) are analyzed. These approaches led to an accumulation of large-scale NGS datasets to solve various challenges of cancer research, molecular characterization, tumor heterogeneity, and drug target discovery. For instance, The Cancer Genome Atlas (TCGA) dataset contains multi-omics data from ten-thousands of patients. This dataset facilitates a variety of cancer researches for decades. Additionally, there are also independent tumor datasets, and, frequently, they are analyzed and compared with the TCGA dataset. As the large scale of omics data accumulated, various machine learning techniques are applied, e.g., graph algorithms and deep neural networks, for dimensionality reduction, clustering, or classification. (Created with BioRender.com.)

Figure 2. (a) A multitude of different types of data is produced by next-generation sequencing, for instance, in the fields of genomics, transcriptomics, and epigenomics. (b) Biological networks for biomarker validation: The in vivo or in vitro experiment results are considered ground truth. Statistical analysis on next-generation sequencing data produces candidate genes. Biological networks can validate these candidate genes and highlight the underlying biological mechanisms (Section 2.1). (c) De novo construction of Biological Networks: Machine learning models that aim to reconstruct biological networks can incorporate prior knowledge from different omics data. Subsequently, the model will predict new unknown interactions based on new omics information (Section 2.2). (d) Network-based machine learning: Machine learning models integrating biological networks as prior knowledge to improve predictive performance when applied to different NGS data (Section 2.3). (Created with BioRender.com).

Therefore, a large number of studies integrate NGS data with machine learning and propose a novel data-driven methodology in systems biology [8]. In particular, many network-based machine learning models have been developed to analyze cancer data and help to understand novel mechanisms in cancer development [9,10]. Moreover, deep neural networks (DNN) applied for large-scale data analysis improved the accuracy of computational models for mutation prediction [11,12], molecular subtyping [13,14], and drug repurposing [15,16]. 

2. Systems Biology in Cancer Research

Genes and their functions have been classified into gene sets based on experimental data. Our understandings of cancer concentrated into cancer hallmarks that define the characteristics of a tumor. This collective knowledge is used for the functional analysis of unseen data.. Furthermore, the regulatory relationships among genes were investigated, and, based on that, a pathway can be composed. In this manner, the accumulation of public high-throughput sequencing data raised many big-data challenges and opened new opportunities and areas of application for computer science. Two of the most vibrantly evolving areas are systems biology and machine learning which tackle different tasks such as understanding the cancer pathways [9], finding crucial genes in pathways [22,53], or predicting functions of unidentified or understudied genes [54]. Essentially, those models include prior knowledge to develop an analysis and enhance interpretability for high-dimensional data [2]. In addition to understanding cancer pathways with in silico analysis, pathway activity analysis incorporating two different types of data, pathways and omics data, is developed to understand heterogeneous characteristics of the tumor and cancer molecular subtyping. Due to its advantage in interpretability, various pathway-oriented methods are introduced and become a useful tool to understand a complex diseases such as cancer [55,56,57].

In this section, we will discuss how two related research fields, namely, systems biology and machine learning, can be integrated with three different approaches (see Figure 2), namely, biological network analysis for biomarker validation, the use of machine learning with systems biology, and network-based models.

2.1. Biological Network Analysis for Biomarker Validation

The detection of potential biomarkers indicative of specific cancer types or subtypes is a frequent goal of NGS data analysis in cancer research. For instance, a variety of bioinformatics tools and machine learning models aim at identify lists of genes that are significantly altered on a genomic, transcriptomic, or epigenomic level in cancer cells. Typically, statistical and machine learning methods are employed to find an optimal set of biomarkers, such as single nucleotide polymorphisms (SNPs), mutations, or differentially expressed genes crucial in cancer progression. Traditionally, resource-intensive in vitro analysis was required to discover or validate those markers. Therefore, systems biology offers in silico solutions to validate such findings using biological pathways or gene ontology information (Figure 2b) [58]. Subsequently, gene set enrichment analysis (GSEA) [50] or gene set analysis (GSA) [59] can be used to evaluate whether these lists of genes are significantly associated with cancer types and their specific characteristics. GSA, for instance, is available via web services like DAVID [60] and g:Profiler [61]. Moreover, other applications use gene ontology directly [62,63]. In addition to gene-set-based analysis, there are other methods that focuse on the topology of biological networks. These approaches evaluate various network structure parameters and analyze the connectivity of two genes or the size and interconnection of their neighbors [64,65]. According to the underlying idea, the mutated gene will show dysfunction and can affect its neighboring genes. Thus, the goal is to find abnormalities in a specific set of genes linked with an edge in a biological network. For instance, KeyPathwayMiner can extract informative network modules in various omics data [66]. In summary, these approaches aim at predicting the effect of dysfunctional genes among neighbors according to their connectivity or distances from specific genes such as hubs [67,68]. During the past few decades, the focus of cancer systems biology extended towards the analysis of cancer-related pathways since those pathways tend to carry more information than a gene set. Such analysis is called Pathway Enrichment Analysis (PEA) [69,70]. The use of PEA incorporates the topology of biological networks. However, simultaneously, the lack of coverage issue in pathway data needs to be considered. Because pathway data does not cover all known genes yet, an integration analysis on omics data can significantly drop in genes when incorporated with pathways. Genes that can not be mapped to any pathway are called ‘pathway orphan.’ In this manner, Rahmati et al. introduced a possible solution to overcome the ‘pathway orphan’ issue [71]. At the bottom line, regardless of whether researchers consider gene-set or pathway-based enrichment analysis, the performance and accuracy of both methods are highly dependent on the quality of the external gene-set and pathway data [72].

2.2. De Novo Construction of Biological Networks

While the known fraction of existing biological networks barely scratches the surface of the whole system of mechanisms occurring in each organism, machine learning models can improve on known network structures and can guide potential new findings [73,74]. This area of research is called de novo network construction (Figure 2c), and its predictive models can accelerate experimental validation by lowering time costs [75,76]. This interplay between in silico biological networks building and mining contributes to expanding our knowledge in a biological system. For instance, a gene co-expression network helps discover gene modules having similar functions [77]. Because gene co-expression networks are based on expressional changes under specific conditions, commonly, inferring a co-expression network requires many samples. The WGCNA package implements a representative model using weighted correlation for network construction that leads the development of the network biology field [78]. Due to NGS developments, the analysis of gene co-expression networks subsequently moved from microarray-based to RNA-seq based experimental data [79]. However, integration of these two types of data remains tricky. Ballouz et al. compared microarray and NGS-based co-expression networks and found the existence of a bias originating from batch effects between the two technologies [80]. Nevertheless, such approaches are suited to find disease-specific co-expressional gene modules. Thus, various studies based on the TCGA cancer co-expression network discovered characteristics of prognostic genes in the network [81]. Accordingly, a gene co-expression network is a condition-specific network rather than a general network for an organism. Gene regulatory networks can be inferred from the gene co-expression network when various data from different conditions in the same organism are available. Additionally, with various NGS applications, we can obtain multi-modal datasets about regulatory elements and their effects, such as epigenomic mechanisms on transcription and chromatin structure. Consequently, a gene regulatory network can consist of solely protein-coding genes or different regulatory node types such as transcription factors, inhibitors, promoter interactions, DNA methylations, and histone modifications affecting the gene expression system [82,83]. More recently, researchers were able to build networks based on a particular experimental setup. For instance, functional genomics or CRISPR technology enables the high-resolution regulatory networks in an organism [84]. Other than gene co-expression or regulatory networks, drug target, and drug repurposing studies are active research areas focusing on the de novo construction of drug-to-target networks to allow the potential repurposing of drugs [76,85].

2.3. Network Based Machine Learning

A network-based machine learning model directly integrates the insights of biological networks within the algorithm (Figure 2d) to ultimately improve predictive performance concerning cancer subtyping or susceptibility to therapy. Following the establishment of high-quality biological networks based on NGS technologies, these biological networks were suited to be integrated into advanced predictive models. In this manner, Zhang et al., categorized network-based machine learning approaches upon their usage into three groups: (i) model-based integration, (ii) pre-processing integration, and (iii) post-analysis integration [7]. Network-based models map the omics data onto a biological network, and proper algorithms travel the network while considering both values of nodes and edges and network topology. In the pre-processing integration, pathway or other network information is commonly processed based on its topological importance. Meanwhile, in the post-analysis integration, omics data is processed solely before integration with a network. Subsequently, omics data and networks are merged and interpreted. The network-based model has advantages in multi-omics integrative analysis. Due to the different sensitivity and coverage of various omics data types, a multi-omics integrative analysis is challenging. However, focusing on gene-level or protein-level information enables a straightforward integration [86,87]. Consequently, when different machine learning approaches tried to integrate two or more different data types to find novel biological insights, one of the solutions is reducing the search space to gene or protein level and integrated heterogeneous datatypes [25,88].

In summary, using network information opens new possibilities for interpretation. However, as mentioned earlier, several challenges remain, such as the coverage issue. Current databases for biological networks do not cover the entire set of genes, transcripts, and interactions. Therefore, the use of networks can lead to loss of information for gene or transcript orphans. The following section will focus on network-based machine learning models and their application in cancer genomics. We will put network-based machine learning into the perspective of the three main areas of application, namely, molecular characterization, tumor heterogeneity analysis, and cancer drug discovery.

3. Network-Based Learning in Cancer Research

As introduced previously, the integration of machine learning with the insights of biological networks (Figure 2d) ultimately aims at improving predictive performance and interpretability concerning cancer subtyping or treatment susceptibility.

3.1. Molecular Characterization with Network Information

Various network-based algorithms are used in genomics and focus on quantifying the impact of genomic alteration. By employing prior knowledge in biological network algorithms, performance compared to non-network models can be improved. A prominent example is HotNet. The algorithm uses a thermodynamics model on a biological network and identifies driver genes, or prognostic genes, in pan-cancer data [89]. Another study introduced a network-based stratification method to integrate somatic alterations and expression signatures with network information [90]. These approaches use network topology and network-propagation-like algorithms. Network propagation presumes that genomic alterations can affect the function of neighboring genes. Two genes will show an exclusive pattern if two genes complement each other, and the function carried by those two genes is essential to an organism [91]. This unique exclusive pattern among genomic alteration is further investigated in cancer-related pathways. Recently, Ku et al. developed network-centric approaches and tackled robustness issues while studying synthetic lethality [92]. Although synthetic lethality was initially discovered in model organisms of genetics, it helps us to understand cancer-specific mutations and their functions in tumor characteristics [91].

Furthermore, in transcriptome research, network information is used to measure pathway activity and its application in cancer subtyping. For instance, when comparing the data of two or more conditions such as cancer types, GSEA as introduced in Section 2 is a useful approach to get an overview of systematic changes [50]. It is typically used at the beginning of a data evaluation [93]. An experimentally validated gene set can provide information about how different conditions affect molecular systems in an organism. In addition to the gene sets, different approaches integrate complex interaction information into GSEA and build network-based models [70]. In contrast to GSEA, pathway activity analysis considers transcriptome data and other omics data and structural information of a biological network. For example, PARADIGM uses pathway topology and integrates various omics in the analysis to infer a patient-specific status of pathways [94]. A benchmark study with pan-cancer data recently reveals that using network structure can show better performance [57]. In conclusion, while the loss of data is due to the incompleteness of biological networks, their integration improved performance and increased interpretability in many cases.

3.2. Tumor Heterogeneity Study with Network Information

The tumor heterogeneity can originate from two directions, clonal heterogeneity and tumor impurity. Clonal heterogeneity covers genomic alterations within the tumor [95]. While de novo mutations accumulate, the tumor obtains genomic alterations with an exclusive pattern. When these genomic alterations are projected on the pathway, it is possible to observe exclusive relationships among disease-related genes. For instance, the CoMEt and MEMo algorithms examine mutual exclusivity on protein–protein interaction networks [96,97]. Moreover, the relationship between genes can be essential for an organism. Therefore, models analyzing such alterations integrate network-based analysis [98].

In contrast, tumor purity is dependent on the tumor microenvironment, including immune-cell infiltration and stromal cells [99]. In tumor microenvironment studies, network-based models are applied, for instance, to find immune-related gene modules. Although the importance of the interaction between tumors and immune cells is well known, detailed mechanisms are still unclear. Thus, many recent NGS studies employ network-based models to investigate the underlying mechanism in tumor and immune reactions. For example, McGrail et al. identified a relationship between the DNA damage response protein and immune cell infiltration in cancer. The analysis is based on curated interaction pairs in a protein–protein interaction network [100]. Most recently, Darzi et al. discovered a prognostic gene module related to immune cell infiltration by using network-centric approaches [101]. Tu et al. presented a network-centric model for mining subnetworks of genes other than immune cell infiltration by considering tumor purity [102].

3.3. Drug Target Identification with Network Information

In drug target studies, network biology is integrated into pharmacology [103]. For instance, Yamanishi et al. developed novel computational methods to investigate the pharmacological space by integrating a drug-target protein network with genomics and chemical information. The proposed approaches investigated such drug-target network information to identify potential novel drug targets [104]. Since then, the field has continued to develop methods to study drug target and drug response integrating networks with chemical and multi-omic datasets. In a recent survey study by Chen et al., the authors compared 13 computational methods for drug response prediction. It turned out that gene expression profiles are crucial information for drug response prediction [105].

Moreover, drug-target studies are often extended to drug-repurposing studies. In cancer research, drug-repurposing studies aim to find novel interactions between non-cancer drugs and molecular features in cancer. Drug-repurposing (or repositioning) studies apply computational approaches and pathway-based models and aim at discovering potential new cancer drugs with a higher probability than de novo drug design [16,106]. Specifically, drug-repurposing studies can consider various areas of cancer research, such as tumor heterogeneity and synthetic lethality. As an example, Lee et al. found clinically relevant synthetic lethality interactions by integrating multiple screening NGS datasets [107]. This synthetic lethality and related-drug datasets can be integrated for an effective combination of anticancer therapeutic strategy with non-cancer drug repurposing.

4. Deep Learning in Cancer Research

DNN models develop rapidly and become more sophisticated. They have been frequently used in all areas of biomedical research. Initially, its development was facilitated by large-scale imaging and video data. While most data sets in the biomedical field would not typically be considered big data, the rapid data accumulation enabled by NGS made it suitable for the application of DNN models requiring a large amount of training data [108]. For instance, in 2019, Samiei et al. used TCGA-based large-scale cancer data as benchmark datasets for bioinformatics machine learning research such as Image-Net in the computer vision field [109]. Subsequently, large-scale public cancer data sets such as TCGA encouraged the wide usage of DNNs in the cancer domain [110]. Over the last decade, these state-of-the-art machine learning methods have been incorporated in many different biological questions [111].

In addition to public cancer databases such as TCGA, the genetic information of normal tissues is stored in well-curated databases such as GTEx [112] and 1000Genomes [113]. These databases are frequently used as control or baseline training data for deep learning [114]. Moreover, other non-curated large-scale data sources such as GEO (https://www.ncbi.nlm.nih.gov/geo/, accessed on 20 May 2021) can be leveraged to tackle critical aspects in cancer research. They store a large-scale of biological data produced under various experimental setups (Figure 1). Therefore, an integration of GEO data and other data requires careful preprocessing. Overall, an increasing amount of datasets facilitate the development of current deep learning in bioinformatics research [115].

4.1. Challenges for Deep Learning in Cancer Research

Many studies in biology and medicine used NGS and produced large amounts of data during the past few decades, moving the field to the big data era. Nevertheless, researchers still face a lack of data in particular when investigating rare diseases or disease states. Researchers have developed a manifold of potential solutions to overcome this lack of data challenges, such as imputation, augmentation, and transfer learning (Figure 3b). Data imputation aims at handling data sets with missing values [116]. It has been studied on various NGS omics data types to recover missing information [117]. It is known that gene expression levels can be altered by different regulatory elements, such as DNA-binding proteins, epigenomic modifications, and post-transcriptional modifications. Therefore, various models integrating such regulatory schemes have been introduced to impute missing omics data [118,119]. Some DNN-based models aim to predict gene expression changes based on genomics or epigenomics alteration. For instance, TDimpute aims at generating missing RNA-seq data by training a DNN on methylation data. They used TCGA and TARGET (https://ocg.cancer.gov/programs/target/data-matrix, accessed on 20 May 2021) data as proof of concept of the applicability of DNN for data imputation in a multi-omics integration study [120]. Because this integrative model can exploit information in different levels of regulatory mechanisms, it can build a more detailed model and achieve better performance than a model build on a single-omics dataset [117,121]. The generative adversarial network (GAN) is a DNN structure for generating simulated data that is different from the original data but shows the same characteristics [122]. GANs can impute missing omics data from other multi-omics sources. Recently, the GAN algorithm is getting more attention in single-cell transcriptomics because it has been recognized as a complementary technique to overcome the limitation of scRNA-seq [123]. In contrast to data imputation and generation, other machine learning approaches aim to cope with a limited dataset in different ways. Transfer learning or few-shot learning, for instance, aims to reduce the search space with similar but unrelated datasets and guide the model to solve a specific set of problems [124]. These approaches train models with data of similar characteristics and types but different data to the problem set. After pre-training the model, it can be fine-tuned with the dataset of interest [125,126]. Thus, researchers are trying to introduce few-shot learning models and meta-learning approaches to omics and translational medicine. For example, Select-ProtoNet applied the ProtoTypical Network [127] model to TCGA transcriptome data and classified patients into two groups according to their clinical status [128]. AffinityNet predicts kidney and uterus cancer subtypes with gene expression profiles [129].

Figure 3. (a) In various studies, NGS data transformed into different forms. The 2-D transformed form is for the convolution layer. Omics data is transformed into pathway level, GO enrichment score, or Functional spectra. (b) DNN application on different ways to handle lack of data. Imputation for missing data in multi-omics datasets. GAN for data imputation and in silico data simulation. Transfer learning pre-trained the model with other datasets and fine-tune. (c) Various types of information in biology. (d) Graph neural network examples. GCN is applied to aggregate neighbor information. (Created with BioRender.com).

4.2. Molecular Charactization with Network and DNN Model

DNNs have been applied in multiple areas of cancer research. For instance, a DNN model trained on TCGA cancer data can aid molecular characterization by identifying cancer driver genes. At the very early stage, Yuan et al. build DeepGene, a cancer-type classifier. They implemented data sparsity reduction methods and trained the DNN model with somatic point mutations [130]. Lyu et al. [131] and DeepGx [132] embedded a 1-D gene expression profile to a 2-D array by chromosome order to implement the convolution layer (Figure 3a). Other algorithms, such as the deepDriver, use k-nearest neighbors for the convolution layer. A predefined number of neighboring gene mutation profiles was the input for the convolution layer. It employed this convolution layer in a DNN by aggregating mutation information of the k-nearest neighboring genes [11]. Instead of embedding to a 2-D image, DeepCC transformed gene expression data into functional spectra. The resulting model was able to capture molecular characteristics by training cancer subtypes [14].

Another DNN model was trained to infer the origin of tissue from single-nucleotide variant (SNV) information of metastatic tumor. The authors built a model by using the TCGA/ICGC data and analyzed SNV patterns and corresponding pathways to predict the origin of cancer. They discovered that metastatic tumors retained their original cancer’s signature mutation pattern. In this context, their DNN model obtained even better accuracy than a random forest model [133] and, even more important, better accuracy than human pathologists [12].

4.3. Tumor Heterogeneity with Network and DNN Model

As described in Section 4.1, there are several issues because of cancer heterogeneity, e.g., tumor microenvironment. Thus, there are only a few applications of DNN in intratumoral heterogeneity research. For instance, Menden et al. developed ’Scaden’ to deconvolve cell types in bulk-cell sequencing data. ’Scaden’ is a DNN model for the investigation of intratumor heterogeneity. To overcome the lack of training datasets, researchers need to generate in silico simulated bulk-cell sequencing data based on single-cell sequencing data [134]. It is presumed that deconvolving cell types can be achieved by knowing all possible expressional profiles of the cell [36]. However, this information is typically not available. Recently, to tackle this problem, single-cell sequencing-based studies were conducted. Because of technical limitations, we need to handle lots of missing data, noises, and batch effects in single-cell sequencing data [135]. Thus, various machine learning methods were developed to process single-cell sequencing data. They aim at mapping single-cell data onto the latent space. For example, scDeepCluster implemented an autoencoder and trained it on gene-expression levels from single-cell sequencing. During the training phase, the encoder and decoder work as denoiser. At the same time, they can embed high-dimensional gene-expression profiles to lower-dimensional vectors [136]. This autoencoder-based method can produce biologically meaningful feature vectors in various contexts, from tissue cell types [137] to different cancer types [138,139].

4.4. Drug Target Identification with Networks and DNN Models

In addition to NGS datasets, large-scale anticancer drug assays enabled the training train of DNNs. Moreover, non-cancer drug response assay datasets can also be incorporated with cancer genomic data. In cancer research, a multidisciplinary approach was widely applied for repurposing non-oncology drugs to cancer treatment. This drug repurposing is faster than de novo drug discovery. Furthermore, combination therapy with a non-oncology drug can be beneficial to overcome the heterogeneous properties of tumors [85]. The deepDR algorithm integrated ten drug-related networks and trained deep autoencoders. It used a random-walk-based algorithm to represent graph information into feature vectors. This approach integrated network analysis with a DNN model validated with an independent drug-disease dataset [15].

The authors of CDRscan did an integrative analysis of cell-line-based assay datasets and other drug and genomics datasets. It shows that DNN models can enhance the computational model for improved drug sensitivity predictions [140]. Additionally, similar to previous network-based models, the multi-omics application of drug-targeted DNN studies can show higher prediction accuracy than the single-omics method. MOLI integrated genomic data and transcriptomic data to predict the drug responses of TCGA patients [141].

4.5. Graph Neural Network Model

In general, the advantage of using a biological network is that it can produce more comprehensive and interpretable results from high-dimensional omics data. Furthermore, in an integrative multi-omics data analysis, network-based integration can improve interpretability over traditional approaches. Instead of pre-/post-integration of a network, recently developed graph neural networks use biological networks as the base structure for the learning network itself. For instance, various pathways or interactome information can be integrated as a learning structure of a DNN and can be aggregated as heterogeneous information. In a GNN study, a convolution process can be done on the provided network structure of data. Therefore, the convolution on a biological network made it possible for the GNN to focus on the relationship among neighbor genes. In the graph convolution layer, the convolution process integrates information of neighbor genes and learns topological information (Figure 3d). Consequently, this model can aggregate information from far-distant neighbors, and thus can outperform other machine learning models [142].

In the context of the inference problem of gene expression, the main question is whether the gene expression level can be explained by aggregating the neighboring genes. A single gene inference study by Dutil et al. showed that the GNN model outperformed other DNN models [143]. Moreover, in cancer research, such GNN models can identify cancer-related genes with better performance than other network-based models, such as HotNet2 and MutSigCV [144]. A recent GNN study with a multi-omics integrative analysis identified 165 new cancer genes as an interactive partner for known cancer genes [145]. Additionally, in the synthetic lethality area, dual-dropout GNN outperformed previous bioinformatics tools for predicting synthetic lethality in tumors [146]. GNNs were also able to classify cancer subtypes based on pathway activity measures with RNA-seq data. Lee et al. implemented a GNN for cancer subtyping and tested five cancer types. Thus, the informative pathway was selected and used for subtype classification [147]. Furthermore, GNNs are also getting more attention in drug repositioning studies. As described in Section 3.3, drug discovery requires integrating various networks in both chemical and genomic spaces (Figure 3d). Chemical structures, protein structures, pathways, and other multi-omics data were used in drug-target identification and repurposing studies (Figure 3c). Each of the proposed applications has a specialty in the different purposes of drug-related tasks. Sun et al. summarized GNN-based drug discovery studies and categorized them into four classes: molecular property and activity prediction, interaction prediction, synthesis prediction, and de novo drug design. The authors also point out four challenges in the GNN-mediated drug discovery. At first, as we described before, there is a lack of drug-related datasets. Secondly, the current GNN models can not fully represent 3-D structures of chemical molecules and protein structures. The third challenge is integrating heterogeneous network information. Drug discovery usually requires a multi-modal integrative analysis with various networks, and GNNs can improve this integrative analysis. Lastly, although GNNs use graphs, stacked layers still make it hard to interpret the model [148].

4.6. Shortcomings in AI and Revisiting Validity of Biological Networks as Prior Knowledge

The previous sections reviewed a variety of DNN-based approaches that present a good performance on numerous applications. However, it is hardly a panacea for all research questions. In the following, we will discuss potential limitations of the DNN models. In general, DNN models with NGS data have two significant issues: (i) data requirements and (ii) interpretability. Usually, deep learning needs a large proportion of training data for reasonable performance which is more difficult to achieve in biomedical omics data compared to, for instance, image data. Today, there are not many NGS datasets that are well-curated and -annotated for deep learning. This can be an answer to the question of why most DNN studies are in cancer research [110,149]. Moreover, the deep learning models are hard to interpret and are typically considered as black-boxes. Highly stacked layers in the deep learning model make it hard to interpret its decision-making rationale. Although the methodology to understand and interpret deep learning models has been improved, the ambiguity in the DNN models’ decision-making hindered the transition between the deep learning model and translational medicine [149,150].

As described before, biological networks are employed in various computational analyses for cancer research. The studies applying DNNs demonstrated many different approaches to use prior knowledge for systematic analyses. Before discussing GNN application, the validity of biological networks in a DNN model needs to be shown. The LINCS program analyzed data of ’The Connectivity Map (CMap) project’ to understand the regulatory mechanism in gene expression by inferring the whole gene expression profiles from a small set of genes (https://lincsproject.org/, accessed on 20 May 2021) [151,152]. This LINCS program found that the gene expression level is inferrable with only nearly 1000 genes. They called this gene list ’landmark genes’. Subsequently, Chen et al. started with these 978 landmark genes and tried to predict other gene expression levels with DNN models. Integrating public large-scale NGS data showed better performance than the linear regression model. The authors conclude that the performance advantage originates from the DNN’s ability to model non-linear relationships between genes [153].

Following this study, Beltin et al. extensively investigated various biological networks in the same context of the inference of gene expression level. They set up a simplified representation of gene expression status and tried to solve a binary classification task. To show the relevance of a biological network, they compared various gene expression levels inferred from a different set of genes, neighboring genes in PPI, random genes, and all genes. However, in the study incorporating TCGA and GTEx datasets, the random network model outperformed the model build on a known biological network, such as StringDB [154]. While network-based approaches can add valuable insights to analysis, this study shows that it cannot be seen as the panacea, and a careful evaluation is required for each data set and task. In particular, this result may not represent biological complexity because of the oversimplified problem setup, which did not consider the relative gene-expressional changes. Additionally, the incorporated biological networks may not be suitable for inferring gene expression profiles because they consist of expression-regulating interactions, non-expression-regulating interactions, and various in vivo and in vitro interactions.

“ However, although recently sophisticated applications of deep learning showed improved accuracy, it does not reflect a general advancement. Depending on the type of NGS data, the experimental design, and the question to be answered, a proper approach and specific deep learning algorithms need to be considered. Deep learning is not a panacea. In general, to employ machine learning and systems biology methodology for a specific type of NGS data, a certain experimental design, a particular research question, the technology, and network data have to be chosen carefully.”

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Use of Systems Biology in Anti-Microbial Drug Development

Genomics, Computational Biology and Drug Discovery for Mycobacterial Infections: Fighting the Emergence of Resistance. Asma Munir, Sundeep Chaitanya Vedithi, Amanda K. Chaplin and Tom L. Blundell. Front. Genet., 04 September 2020 | https://doi.org/10.3389/fgene.2020.00965

In an earlier review article (Waman et al., 2019), we discussed various computational approaches and experimental strategies for drug target identification and structure-guided drug discovery. In this review we discuss the impact of the era of precision medicine, where the genome sequences of pathogens can give clues about the choice of existing drugs, and repurposing of others. Our focus is directed toward combatting antimicrobial drug resistance with emphasis on tuberculosis and leprosy. We describe structure-guided approaches to understanding the impacts of mutations that give rise to antimycobacterial resistance and the use of this information in the design of new medicines.

Genome Sequences and Proteomic Structural Databases

In recent years, there have been many focused efforts to define the amino-acid sequences of the M. tuberculosis pan-genome and then to define the three-dimensional structures and functional interactions of these gene products. This work has led to essential genes of the bacteria being revealed and to a better understanding of the genetic diversity in different strains that might lead to a selective advantage (Coll et al., 2018). This will help with our understanding of the mode of antibiotic resistance within these strains and aid structure-guided drug discovery. However, only ∼10% of the ∼4128 proteins have structures determined experimentally.

Several databases have been developed to integrate the genomic and/or structural information linked to drug resistance in Mycobacteria (Table 1). These invaluable resources can contribute to better understanding of molecular mechanisms involved in drug resistance and improvement in the selection of potential drug targets.

There is a dearth of information related to structural aspects of proteins from M. leprae and their oligomeric and hetero-oligomeric organization, which has limited the understanding of physiological processes of the bacillus. The structures of only 12 proteins have been solved and deposited in the protein data bank (PDB). However, the high sequence similarity in protein coding genes between M. leprae and M. tuberculosis allows computational methods to be used for comparative modeling of the proteins of M. leprae. Mainly monomeric models using single template modeling have been defined and deposited in the Swiss Model repository (Bienert et al., 2017), in Modbase (Pieper et al., 2014), and in a collection with other infectious disease agents (Sosa et al., 2018). There is a need for multi-template modeling and building homo- and hetero-oligomeric complexes to better understand the interfaces, druggability and impacts of mutations.

We are now exploiting Vivace, a multi-template modeling pipeline developed in our lab for modeling the proteomes of M. tuberculosis (CHOPIN, see above) and M. abscessus [Mabellini Database (Skwark et al., 2019)], to model the proteome of M. leprae. We emphasize the need for understanding the protein interfaces that are critical to function. An example of this is that of the RNA-polymerase holoenzyme complex from M. leprae. We first modeled the structure of this hetero-hexamer complex and later deciphered the binding patterns of rifampin (Vedithi et al., 2018Figures 1A,B). Rifampin is a known drug to treat tuberculosis and leprosy. Owing to high rifampin resistance in tuberculosis and emerging resistance in leprosy, we used an approach known as “Computational Saturation Mutagenesis”, to identify sites on the protein that are less impacted by mutations. In this study, we were able to understand the association between predicted impacts of mutations on the structure and phenotypic rifampin-resistance outcomes in leprosy.

FIGURE 2

Figure 2. (A) Stability changes predicted by mCSM for systematic mutations in the ß-subunit of RNA polymerase in M. leprae. The maximum destabilizing effect from among all 19 possible mutations at each residue position is considered as a weighting factor for the color map that gradients from red (high destabilizing effects) to white (neutral to stabilizing effects) (Vedithi et al., 2020). (B) One of the known mutations in the ß-subunit of RNA polymerase, the S437H substitution which resulted in a maximum destabilizing effect [-1.701 kcal/mol (mCSM)] among all 19 possibilities this position. In the mutant, histidine (residue in green) forms hydrogen bonds with S434 and Q438, aromatic interactions with F431, and other ring-ring and π interactions with the surrounding residues which can impact the shape of the rifampin binding pocket and rifampin affinity to the ß-subunit [-0.826 log(affinity fold change) (mCSM-lig)]. Orange dotted lines represent weak hydrogen bond interactions. Ring-ring and intergroup interactions are depicted in cyan. Aromatic interactions are represented in sky-blue and carbonyl interactions in pink dotted lines. Green dotted lines represent hydrophobic interactions (Vedithi et al., 2020).

Examples of Understanding and Combatting Resistance

The availability of whole genome sequences in the present era has greatly enhanced the understanding of emergence of drug resistance in infectious diseases like tuberculosis. The data generated by the whole genome sequencing of clinical isolates can be screened for the presence of drug-resistant mutations. A preliminary in silico analysis of mutations can then be used to prioritize experimental work to identify the nature of these mutations.

FIGURE 3

Figure 3. (A) Mechanism of isoniazid activation and INH-NAD adduct formation. (B) Mutations mapped (Munir et al., 2019) on the structure of KatG (PDB ID:1SJ2; Bertrand et al., 2004).

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Yet another Success Story: Machine Learning to predict immunotherapy response

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

Immune-checkpoint blockers (ICBs) immunotherapy appears promising for various cancer types, offering a durable therapeutic advantage. Only a number of cases with cancer respond to this therapy. Biomarkers are required to adequately predict the responses of patients. This article evaluates this issue utilizing a system method to characterize the immune response of the anti-tumor based on the entire tumor environment. Researchers build mechanical biomarkers and cancer-specific response models using interpretable machine learning that predict the response of patients to ICB.

The lymphatic and immunological systems help the body defend itself by combating. The immune system functions as the body’s own personal police force, hunting down and eliminating pathogenic baddies.

According to Federica Eduati, Department of Biomedical Engineering at TU/e, “The immune system of the body is quite adept at detecting abnormally behaving cells. Cells that potentially grow into tumors or cancer in the future are included in this category. Once identified, the immune system attacks and destroys the cells.”

Immunotherapy and machine learning are combining to assist the immune system solve one of its most vexing problems: detecting hidden tumorous cells in the human body.

It is the fundamental responsibility of our immune system to identify and remove alien invaders like bacteria or viruses, but also to identify risks within the body, such as cancer. However, cancer cells have sophisticated ways of escaping death by shutting off immune cells. Immunotherapy can reverse the process, but not for all patients and types of cancer. To unravel the mystery, Eindhoven University of Technology researchers used machine learning. They developed a model to predict whether immunotherapy will be effective for a patient using a simple trick. Even better, the model outperforms conventional clinical approaches.

The outcomes of this research are published on 30th June, 2021 in the journal Patterns in an article entitled “Interpretable systems biomarkers predict response to immune-checkpoint inhibitors”.

The Study

  • Characterization of the tumor microenvironment from RNAseq and prior knowledge
  • Multi-task machine-learning models for predicting antitumor immune responses
  • Identification of cancer-type-specific, interpretable biomarkers of immune responses
  • EaSIeR is a tool to predict biomarker-based immunotherapy response from RNA-seq

“Tumor also contains multiple types of immune and fibroblast cells which can play a role in favor of or anti-tumor, and communicates among themselves,” said Oscar Lapuente-Santana, a researcher doctoral student in the computational biology group. “We had to learn how complicated regulatory mechanisms in the micro-environment of the tumor affect the ICB response. We have used RNA sequencing datasets to depict numerous components of the Tumor Microenvironment (TME) in a high-level illustration.”

Using computational algorithms and datasets from previous clinical patient care, the researchers investigated the TME.

Eduati explained

While RNA-sequencing databases are publically available, information on which patients responded to ICB therapy is only available for a limited group of patients and cancer types. So, to tackle the data problem, we used a trick.

All 100 models learned in the randomized cross-validation were included in the EaSIeR tool. For each validation dataset, we used the corresponding cancer-type-specific model: SKCM for the melanoma Gide, Auslander, Riaz, and Liu cohorts; STAD for the gastric cancer Kim cohort; BLCA for the bladder cancer Mariathasan cohort; and GBM for the glioblastoma Cloughesy cohort. To make predictions for each job, the average of the 100 cancer-type-specific models was employed. The predictions of each dataset’s cancer-type-specific models were also compared to models generated for the remaining 17 cancer types.

From the same datasets, the researchers selected several surrogate immunological responses to be used as a measure of ICB effectiveness.

Lapuente-Santana stated

One of the most difficult aspects of our job was properly training the machine learning models. We were able to fix this by looking at alternative immune responses during the training process.

Some of the researchers employed the machine learning approach given in the paper to participate in the “Anti-PD1 Response Prediction DREAM Challenge.”

DREAM is an organization that carries out crowd-based tasks with biomedical algorithms. “We were the first to compete in one of the sub-challenges under the name cSysImmunoOnco team,” Eduati remarks.

The researchers noted,

We applied machine learning to seek for connections between the obtained system-based attributes and the immune response, estimated using 14 predictors (proxies) derived from previous publications. We treated these proxies as individual tasks to be predicted by our machine learning models, and we employed multi-task learning algorithms to jointly learn all tasks.

The researchers discovered that their machine learning model surpasses biomarkers that are already utilized in clinical settings to evaluate ICB therapies.

But why are Eduati, Lapuente-Santana, and their colleagues using mathematical models to tackle a medical treatment problem? Is this going to take the place of the doctor?

Eduati explains

Mathematical models can provide an overview of the interconnection between individual molecules and cells and at the same time predicting a particular patient’s tumor behavior. This implies that immunotherapy with ICB can be personalized in a patient’s clinical setting. The models can aid physicians with their decisions about optimum therapy, it is vital to note that they will not replace them.

Furthermore, the model aids in determining which biological mechanisms are relevant for the biological response.

The researchers noted

Another advantage of our concept is that it does not need a dataset with known patient responses to immunotherapy for model training.

Further testing is required before these findings may be implemented in clinical settings.

Main Source:

Lapuente-Santana, Ó., van Genderen, M., Hilbers, P. A., Finotello, F., & Eduati, F. (2021). Interpretable systems biomarkers predict response to immune-checkpoint inhibitorsPatterns, 100293. https://www.cell.com/patterns/pdfExtended/S2666-3899(21)00126-4

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Renal tumor macrophages linked to recurrence are identified using single-cell protein activity analysis

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

When malignancy returns after a period of remission, it is called a cancer recurrence. After the initial or primary cancer has been treated, this can happen weeks, months, or even years later. The possibility of recurrence is determined by the type of primary cancer. Because small patches of cancer cells might stay in the body after treatment, cancer might reoccur. These cells may multiply and develop large enough to cause symptoms or cause cancer over time. The type of cancer determines when and where cancer recurs. Some malignancies have a predictable recurrence pattern.

Even if primary cancer recurs in a different place of the body, recurrent cancer is designated for the area where it first appeared. If breast cancer recurs distantly in the liver, for example, it is still referred to as breast cancer rather than liver cancer. It’s referred to as metastatic breast cancer by doctors. Despite treatment, many people with kidney cancer eventually develop cancer recurrence and incurable metastatic illness.

The most frequent type of kidney cancer is Renal Cell Carcinoma (RCC). RCC is responsible for over 90% of all kidney malignancies. The appearance of cancer cells when viewed under a microscope helps to recognize the various forms of RCC. Knowing the RCC subtype can help the doctor assess if the cancer is caused by an inherited genetic condition and help to choose the best treatment option. The three most prevalent RCC subtypes are as follows:

  • Clear cell RCC
  • Papillary RCC
  • Chromophobe RCC

Clear Cell RCC (ccRCC) is the most prevalent subtype of RCC. The cells are clear or pale in appearance and are referred to as the clear cell or conventional RCC. Around 70% of people with renal cell cancer have ccRCC. The rate of growth of these cells might be sluggish or rapid. According to the American Society of Clinical Oncology (ASCO), clear cell RCC responds favorably to treatments like immunotherapy and treatments that target specific proteins or genes.

Researchers at Columbia University’s Vagelos College of Physicians and Surgeons have developed a novel method for identifying which patients are most likely to have cancer relapse following surgery.

The study

Their findings are detailed in a study published in the journal Cell entitled, “Single-Cell Protein Activity Analysis Identifies Recurrence-Associated Renal Tumor Macrophages.” The researchers show that the presence of a previously unknown type of immune cell in kidney tumors can predict who will have cancer recurrence.

According to co-senior author Charles Drake, MD, PhD, adjunct professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and the Herbert Irving Comprehensive Cancer Center,

the findings imply that the existence of these cells could be used to identify individuals at high risk of disease recurrence following surgery who may be candidates for more aggressive therapy.

As Aleksandar Obradovic, an MD/PhD student at Columbia University Vagelos College of Physicians and Surgeons and the study’s co-first author, put it,

it’s like looking down over Manhattan and seeing that enormous numbers of people from all over travel into the city every morning. We need deeper details to understand how these different commuters engage with Manhattan residents: who are they, what do they enjoy, where do they go, and what are they doing?

To learn more about the immune cells that invade kidney cancers, the researchers employed single-cell RNA sequencing. Obradovic remarked,

In many investigations, single-cell RNA sequencing misses up to 90% of gene activity, a phenomenon known as gene dropout.

The researchers next tackled gene dropout by designing a prediction algorithm that can identify which genes are active based on the expression of other genes in the same family. “Even when a lot of data is absent owing to dropout, we have enough evidence to estimate the activity of the upstream regulator gene,” Obradovic explained. “It’s like when playing ‘Wheel of Fortune,’ because I can generally figure out what’s on the board even if most of the letters are missing.”

The meta-VIPER algorithm is based on the VIPER algorithm, which was developed in Andrea Califano’s group. Califano is the head of Herbert Irving Comprehensive Cancer Center’s JP Sulzberger Columbia Genome Center and the Clyde and Helen Wu professor of chemistry and systems biology. The researchers believe that by including meta-VIPER, they will be able to reliably detect the activity of 70% to 80% of all regulatory genes in each cell, eliminating cell-to-cell dropout.

Using these two methods, the researchers were able to examine 200,000 tumor cells and normal cells in surrounding tissues from eleven patients with ccRCC who underwent surgery at Columbia’s urology department.

The researchers discovered a unique subpopulation of immune cells that can only be found in tumors and is linked to disease relapse after initial treatment. The top genes that control the activity of these immune cells were discovered through the VIPER analysis. This “signature” was validated in the second set of patient data obtained through a collaboration with Vanderbilt University researchers; in this second set of over 150 patients, the signature strongly predicted recurrence.

These findings raise the intriguing possibility that these macrophages are not only markers of more risky disease, but may also be responsible for the disease’s recurrence and progression,” Obradovic said, adding that targeting these cells could improve clinical outcomes

Drake said,

Our research shows that when the two techniques are combined, they are extremely effective at characterizing cells within a tumor and in surrounding tissues, and they should have a wide range of applications, even beyond cancer research.

Main Source

Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages

https://www.cell.com/cell/fulltext/S0092-8674(21)00573-0

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Machine Learning (ML) in cancer prognosis prediction helps the researcher to identify multiple known as well as candidate cancer diver genes

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

This image has an empty alt attribute; its file name is morethanthes.jpg
Seeing “through” the cancer with the power of data analysis — possible with the help of artificial intelligence. Credit: MPI f. Molecular Genetics/ Ella Maru Studio
Image Source: https://medicalxpress.com/news/2021-04-sum-mutations-cancer-genes-machine.html

Cancer has been characterized as a heterogeneous disease consisting of many different subtypes. The early diagnosis and prognosis of a cancer type have become a necessity in cancer research, as it can facilitate the subsequent clinical management of patients. The importance of classifying cancer patients into high or low-risk groups has led many research teams, from the biomedical and the bioinformatics field, to study the application of machine learning (ML) and Artificial Intelligence (AI) methods. Therefore, these techniques have been utilized as an aim to model the progression and treatment of cancerous conditions by predicting new algorithms.

In the majority of human cancers, heritable loss of gene function through cell division may be mediated as often by epigenetic as by genetic abnormalities. Epigenetic modification occurs through a process of interrelated changes in CpG island methylation and histone modifications. Candidate gene approaches of cell cycle, growth regulatory and apoptotic genes have shown epigenetic modification associated with loss of cognate proteins in sporadic pituitary tumors.

On 11th November 2020, researchers from the University of California, Irvine, has established the understanding of epigenetic mechanisms in tumorigenesis and publicized a previously undetected repertoire of cancer driver genes. The study was published in “Science Advances

Researchers were able to identify novel tumor suppressor genes (TSGs) and oncogenes (OGs), particularly those with rare mutations by using a new prediction algorithm, called DORGE (Discovery of Oncogenes and tumor suppressor genes using Genetic and Epigenetic features) by integrating the most comprehensive collection of genetic and epigenetic data.

The senior author Wei Li, Ph.D., the Grace B. Bell chair and professor of bioinformatics in the Department of Biological Chemistry at the UCI School of Medicine said

Existing bioinformatics algorithms do not sufficiently leverage epigenetic features to predict cancer driver genes, even though epigenetic alterations are known to be associated with cancer driver genes.

The Study

This study demonstrated how cancer driver genes, predicted by DORGE, included both known cancer driver genes and novel driver genes not reported in current literature. In addition, researchers found that the novel dual-functional genes, which DORGE predicted as both TSGs and OGs, are highly enriched at hubs in protein-protein interaction (PPI) and drug/compound-gene networks.

Prof. Li explained that the DORGE algorithm, successfully leveraged public data to discover the genetic and epigenetic alterations that play significant roles in cancer driver gene dysregulation and could be instrumental in improving cancer prevention, diagnosis and treatment efforts in the future.

Another new algorithmic prediction for the identification of cancer genes by Machine Learning has been carried out by a team of researchers at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin and the Institute of Computational Biology of Helmholtz Zentrum München combining a wide variety of data analyzed it with “Artificial Intelligence” and identified numerous cancer genes. They termed the algorithm as EMOGI (Explainable Multi-Omics Graph Integration). EMOGI can predict which genes cause cancer, even if their DNA sequence is not changed. This opens up new perspectives for targeted cancer therapy in personalized medicine and the development of biomarkers. The research was published in Nature Machine Intelligence on 12th April 2021.

In cancer, cells get out of control. They proliferate and push their way into tissues, destroying organs and thereby impairing essential vital functions. This unrestricted growth is usually induced by an accumulation of DNA changes in cancer genes—i.e. mutations in these genes that govern the development of the cell. But some cancers have only very few mutated genes, which means that other causes lead to the disease in these cases.

The Study

Overlap of EMOGI’s positive predictions with known cancer genes (KCGs) and candidate cancer genes
Image Source: https://static-content.springer.com/esm/art%3A10.1038%2Fs42256-021-00325-y/MediaObjects/42256_2021_325_MOESM1_ESM.pdf

The aim of the study has been represented in 4 main headings

  • Additional targets for personalized medicine
  • Better results by combination
  • In search of hints for further studies
  • Suitable for other types of diseases as well

The team was headed by Annalisa Marsico. The team used the algorithm to identify 165 previously unknown cancer genes. The sequences of these genes are not necessarily altered-apparently, already a dysregulation of these genes can lead to cancer. All of the newly identified genes interact closely with well-known cancer genes and be essential for the survival of tumor cells in cell culture experiments. The EMOGI can also explain the relationships in the cell’s machinery that make a gene a cancer gene. The software integrates tens of thousands of data sets generated from patient samples. These contain information about DNA methylations, the activity of individual genes and the interactions of proteins within cellular pathways in addition to sequence data with mutations. In these data, a deep-learning algorithm detects the patterns and molecular principles that lead to the development of cancer.

Marsico says

Ideally, we obtain a complete picture of all cancer genes at some point, which can have a different impact on cancer progression for different patients

Unlike traditional cancer treatments such as chemotherapy, personalized treatments are tailored to the exact type of tumor. “The goal is to choose the best treatment for each patient, the most effective treatment with the fewest side effects. In addition, molecular properties can be used to identify cancers that are already in the early stages.

Roman Schulte-Sasse, a doctoral student on Marsico’s team and the first author of the publication says

To date, most studies have focused on pathogenic changes in sequence, or cell blueprints, at the same time, it has recently become clear that epigenetic perturbation or dysregulation gene activity can also lead to cancer.

This is the reason, researchers merged sequence data that reflects blueprint failures with information that represents events in cells. Initially, scientists confirmed that mutations, or proliferation of genomic segments, were the leading cause of cancer. Then, in the second step, they identified gene candidates that are not very directly related to the genes that cause cancer.

Clues for future directions

The researcher’s new program adds a considerable number of new entries to the list of suspected cancer genes, which has grown to between 700 and 1,000 in recent years. It was only through a combination of bioinformatics analysis and the newest Artificial Intelligence (AI) methods that the researchers were able to track down the hidden genes.

Schulte-Sasse says “The interactions of proteins and genes can be mapped as a mathematical network, known as a graph.” He explained by giving an example of a railroad network; each station corresponds to a protein or gene, and each interaction among them is the train connection. With the help of deep learning—the very algorithms that have helped artificial intelligence make a breakthrough in recent years – the researchers were able to discover even those train connections that had previously gone unnoticed. Schulte-Sasse had the computer analyze tens of thousands of different network maps from 16 different cancer types, each containing between 12,000 and 19,000 data points.

Many more interesting details are hidden in the data. Patterns that are dependent on particular cancer and tissue were seen. The researchers were also observed this as evidence that tumors are triggered by different molecular mechanisms in different organs.

Marsico explains

The EMOGI program is not limited to cancer, the researchers emphasize. In theory, it can be used to integrate diverse sets of biological data and find patterns there. It could be useful to apply our algorithm for similarly complex diseases for which multifaceted data are collected and where genes play an important role. An example might be complex metabolic diseases such as diabetes.

Main Source

New prediction algorithm identifies previously undetected cancer driver genes

https://advances.sciencemag.org/content/6/46/eaba6784  

Integration of multiomics data with graph convolutional networks to identify new cancer genes and their associated molecular mechanisms

https://www.nature.com/articles/s42256-021-00325-y#citeas

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New approaches to cancer therapy using mathematics

Reporter: Irina Robu, PhD

Our bodies are made up of trillions of cells grouped together to form tissues and organs such as muscles, bones, the lungs and the liver. Genes inside each cell tell it when to grow, work, divide and die. Usually, our cells follow these commands and we stay healthy. Nevertheless, occasionally the instructions get mixed up, triggers our cells to grow and divide out of control or not die when they should. As more and more of these abnormal cells grow and divide, they can form a lump in the body called a tumor.

Cancer therapy thrives in shrinking tumors and frequently fails in the long run; however, a small number of cancer cells are resistant to treatment. The cancer cells expand to fill the space left by the cells that were destroyed.  Using mathematical analysis and numerical simulations, Dr. Noble and Dr. Viossat, a mathematician at Université Paris-Dauphine proposed new approach to validate the concept of using a combination of biological, computational and mathematical models and they show how spatial constraints within tumors can be exploited to suppress resistance to targeted therapy.

Lately, mathematical oncologists have designed a new method to tackling this problem based on evolutionary principles. Known as adaptive therapy, this as-yet unproven strategy aims to stop or delay the failure of cancer treatment by manipulating competition between drug-sensitive and resistant cells. It uses relatively low doses and has the additional potential benefits of reducing side effects and enhance quality of life.

As a way to solve the problem, Dr. Noble and Dr. Viossat organized a workshop for mathematical modelers to determine the state of art of adaptive therapy, discuss future directions and foster collaborations. The virtual event was attended by one hundred persons who participated in more than twenty talks, interacting via the Sococo virtual meeting platform.

Dr. Noble plans to continue developing mathematical models to improve cancer treatment. His long-term objective is to project optimal treatment regimens for each tumor type and each patient.

SOURCE

https://medicalxpress.com/news/2021-01-mathematics-approaches-cancer-therapy.html

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