Oncogene 2025 Pan-RAS Inhibitors and Polo-like Kinase 1: Promising Targets in Colorectal Cancer

RAS is an oncogene that is commonly mutated in colorectal cancer (CRC). It has been considered a negative feature both due to its impact on prognosis and due to the shallow interface of oncogenic Ras for therapeutic targeting. Newer pan-Ras inhibitor strategies include improved direct targeting of RAS, blockade of downstream effectors, immunotherapy approaches, and even the inclusion of anti-EGFR drugs. Polo-like Kinase 1 (PLK1) is a serine/threonine protein kinase that controls multiple aspects of the cell-cycle. It is upregulated in CRC and has become an important therapeutic target in KRAS mutant CRC, with several PLK1 inhibitors currently in various phases of development and testing. As with other targeted therapies, resistance remains a problem and combination strategies may be bene cial. This review discusses pan-RAS inhibitors and PLK1 in the context of CRC. It discusses RAS’ many roles, its associated pathways and relationship to cancer progression, the current status of existing inhibitors, and future strategies for targeting in cancer therapy. The wide-ranging impacts of RAS provide a basis to better understand and fight against CRC.

PLK1 is an important oncogene and cell cycle regulator with multiple effects on downstream pathways. It is crucial to CRC progression and is both a prognostic marker and therapeutic target. PLK1 is crucial in the development of drug resistance via effects on p53 pathways, microtubule dynamics, DNA replication, and effects on cancer metabolism. Inhibition of PLK1 expression could resensitize cancer cells and improve response to therapy even in difficult to treat KRAS mutant cancers.

Combinations with other targeted agents may represent an innovative approach to modulate specific pathways and the tumor microenvironment to improve outcomes. RAS mutations in mCRC are evolving from simply being a negative feature into an important and dynamic target.

Neoplasia-70 (2025) Age-Diet Interactions Significantly Influence Intratumoral Gene Expression, Gut Microbiome Signature and Tumor Microenvironment in Colorectal Cancer

Colorectal Cancer (CRC) is the third most prevalent malignancy, leading to significant morbidity and mortality globally. Epidemiological studies suggest that chronological age and diet are among the major contributing factors correlated with the incidence of CRC. Our study aimed to provide insights into the association between age, diet, and gut microbiome in CRC using molecular techniques including RNA sequencing, cytokine analysis, and metagenomic analysis. We used a syngeneic MC38 mice model divided into two age groups (old and young) and three diet groups (standard chow, calorie-restricted and high-fat). The major findings of this study are that age and diet impact intratumoral gene signaling (nuclear and mitochondrial), and hub genes we identified are associated with prognosis in CRC. Fecal microbiome analysis showed that old microbiomes have higher alpha diversity compared to young mice. Our results demonstrate that interactions between host (age) and external (diet) factors regulate tumor growth mediated by cytokines, mitochondrial derived proteins, and the gut microbiome. Collectively, our findings advance current understanding of the mechanisms by which aging, diet and gut microbiota impact CRC onset and progression though further investigation is warranted.

International Journal of Molecular Sciences 2025 – Genetic Polymorphisms in MHC Classes I and II Predict Outcomes in Metastatic Colorectal Cancer

The immune system is alerted for virally infected cells in the body by the antigen presentation pathway, which is in turn mediated by the major histocompatibility complex (MHC) class I and II molecules. Cancer cells overcome immune evasion as a major hallmark by downregulation of the antigen presentation pathway. Therefore, the present study aimed to explore the effect of genetic variants in genes involved in MHC class I and II pathways in patients treated with first-line chemotherapy in combination with targeted antibodies in metastatic colorectal cancer (mCRC) patients. Genomic DNA from the blood samples of 775 patients enrolled in three independent, randomized, first-line trials.

In conclusion, our results provide the first evidence for an important role for MHC SNPs as prognostic and predictive biomarkers for first-line treatment in mCRC, with dif- ferential effects based on the biologic agent (cetuximab/bevacizumab) and chemotherapy backbone (irinotecan/oxaliplatin). These biomarkers, when further validated, may con- tribute to personalized treatment approaches for mCRC patients. These findings may also provide insight into the potential efficacy of emerging ERAP1 inhibitors when combined with targeted drug and immunotherapeutic treatment in mCRC patients. The novel findings reported in our study warrant further preclinical and prospective clinical studies for validation.

ASCO JCO Precision Oncology 2025 – Association of Androgen Receptor Expression With Tumor Immune Landscape and Treatment Outcomes of Patients With Breast Cancer

Although estrogen receptor is well studied in breast cancer (BC), the role of androgen receptor (AR) in prognosis and therapy response is less understood. Here, we characterized the clinicopathologic and molecular features of AR gene expression in BC subtypes.

RESULTS: AR-low was associated with basal-like tumors. AR-high tumors were associated with increased mutation rates in several genes—namely PIK3CA and CDH1— across all subtypes, while other associations such as RB1 and MAP3K1 were subtype-dependent. The immune landscape was differentially affected by AR expression in each subtype, but these differences did not correspond to differential responses to immune checkpoint blockade. Patients with AR-high tumors had a longer therapy response for most subtypes, but those with AR-high tumors that were human epidermal growth factor receptor 2–enriched and luminal B trended toward worse chemotherapy or hormone therapy response, respectively.

CONCLUSION: Our data suggests a unique molecular profile of AR-high BC that is subtype-specific and generally associated with improved outcomes. Exploration of specific mutations and immuno-oncology markers associated with AR-high may aid in molecularly selected clinical trial design for patients with advanced Breast Cancer.

International Journal of Cancer Dec.7, 2024 – Comprehensive Characterization of MCL-1 in Patients with Colorectal Cancer: Expression, Molecular Profiles, and Outcomes

Colorectal cancer (CRC) is one of the most diagnosed malignancies, ranks among the three major causes of cancer-related incidence and death worldwide, and is primarily focused on developed coun- tries.1 CRC is a prevalent and frequently lethal cancer worldwide.2 In 2023, there were an estimated 153,020 new cases and 52,550 deaths related to CRC in the United States. CRC, along with pros- tate and lung cancers, accounts for approximately 48% of all can- cers in men, and CRC, along with breast and lung cancers, accounts for approximately 52% of all new cancer diagnoses in women.3 Despite the rapid advancements in screening methods and treat- ment strategies that have caused a considerable decline in death rates due to CRC, downward trends seem to be limited in devel- oped countries. The 5-year survival rates of overall CRC and metastatic CRC are approximately 64% and 12%, respectively. Therefore, more effective treatment approaches and medical interventions are needed.

Myeloid cell leukemia 1 (MCL-1) is a member of the BCL-2 protein family that exerts an anti-apoptotic (pro-survival) function.4 MCL-1 is required for intestinal homeostasis and the prevention of intestinal carcinogenesis in mouse models. Despite extensive research on the inhibition of MCL-1 in various cancers, no comprehensive analysis of MCL-1 expression and its association with molecular pathways in CRC has been reported. In this study, we aimed to further characterize the molecular features of human CRCs in association with MCL-1 expression (MCL-1 high vs. MCL-1 low) to provide insight into the role of MCL-1 in CRC and explore potential co-druggable targets and pathways for the treatment of CRC patients with MCL-1 high.

MDPI Journal Cancers August 2024: Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review

Colorectal cancer is a major health concern globally, and finding ways to improve treatment outcomes is crucial. This review explores the role of biomarkers—biological indicators that can predict how a patient will respond to treatment or indicate the likely course of the disease—in managing colorectal cancer. By examining both well-established and emerging biomarkers, we hope to provide a clearer understanding of how these markers can guide personalized treatment plans. The findings from this research could help doctors make more informed decisions, ultimately improving patient care and outcomes in colorectal cancer.

Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.

NPJ Precision Oncology 2024 Large-scale analysis of CDH1 Mutations Defines a Distinctive Molecular Subset with Treatment Implications in Gastric Cancer

Gastric cancer (GC) is a highly heterogeneous disease with marked histological and molecular diversity, which has been a major obstacle in identifying effective novel drug treatments. Except for surgery, chemotherapy remains the major option for treating most patients with advanced GC. Currently, drugs targeting human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor 2 (VEGFR2), CLDN18.2, and immunotherapy have been found to significantly prolong the overall survival, but only appear to be effective in sub-populations while the majority of cases continue to manifest drug resistance to targeted therapies1–4. Thus, there is a significant clinical need to discover novel therapeutic targets for Gastric cancer.

Journal for ImmunoTherapy of Cancer- October 2024: Role of CD47 Gene Expression in Colorectal Cancer: A Comprehensive Molecular Profiling Study

In patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-­ high tumors. Meanwhile, new immunotherapies targeting the innate immune system are attracting increasing attention. CD47 is a representative innate immune checkpoint involved in the evasion of tumor cell phagocytosis by macrophages. This large-­ scale study comprehensively examined the molecular significance of CD47 gene expression in CRC.

What is already known: In the context of the antitumor immune response, the crucial role of the innate immune system has gained attention, and new immunotherapies tar- geting the phagocytosis checkpoint CD47 are being developed.

What this Study Adds: We conducted a large-­ scale molecular profiling study using clinical specimens of colorectal can- cer and found that CD47 gene expression levels positively correlate with the activation of the ma- jor oncogenic signaling pathway, including the mitogen activated protein kinase and angiogenesis pathways. Additionally, tumors with high CD47 gene expression exhibited significantly increased immune cell infiltration within the tumor microenvironment

How this might affect Research, Practice or Policy: A new combination therapy was suggested for colorectal cancers with elevated CD47 expression, which involves the simultaneous inhibition of the innate immune system, the adaptive immune system, and related pathways, including the angiogenesis pathway.

European Journal of Cancer-201 2024 Predictive Value of CDC37 Gene Expression for Targeted Therapy in Metastatic Colorectal Cancer

CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC).

Results: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44–0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11–0.54, p <0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28–0.94, p =0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature.

Journal for Immunotherapy of Cancer 2024- CCR5 and CCL5 Gene Expression in Colorectal Cancer: Comprehensive Profiling and Clinical Value

The C-­ C motif chemokine receptor 5 (CCR5)/ C-­ C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes.

What is already known on this topic: Signaling through the C-­ C motif chemokine ligand 5 (CCL5) and C-­ C motif chemokine receptor 5
(CCR5) can enable tumor progression and metastasis through multiple mechanisms including cancer stem cell progression, increased angiogenesis, recruitment of immunosuppressive cells, and immunosuppressive polarization of macrophages within the tumor microenvironment (TME). Our group previously showed that single nucleotide polymorphisms in CCR5/CCL5 are associated with outcome in patients with metastatic colorectal cancer (CRC) treated with targeted therapies, furthermore the CCR5/CCL5 axis has been recently emerging as a novel therapeutic target in CRC in combination with
immunotherapy strategies

What this Study Adds: Our study leveraged genomic and transcriptomic data from a comprehensive tumor profiling platform to examine the molecular features associated with CCR5 and CCL5 gene expression in CRC. We showed that CCR5 and CCL5 expression is associated with distinct molecular features, immune-­ related gene expression profiles and TME immune cell infiltration in CRC. Furthermore, CCR5/CCL5 expression identi- fied distinct subsets of CRC that derive differential benefit from anticancer treatment.

How this might affect Research, Practice or Policy: These novel findings support the therapeutic potential of targeting the CCR5/CCL5 axis in selected CRC subgroups and its key role in modulating the immune TME, hence providing a rationale for the design of tailored treatment combinations for future clinical research.

Oncogene 2023 – Breast cancer and neurotransmitters: emerging insights on mechanisms and therapeutic directions

Piecing together the puzzle of neurotransmitters’ influence on breast cancer is vital to better understand breast cancer biology and discover novel treatment approaches. It is also urgent to clarify the effects—positive, negative, or neutral—on breast cancer of commonly used medications, including beta blockers, SSRIs, MAOIs, and many more. Even the anesthesia used for breast cancer surgery may need thoughtful examination.

– Exploring the relationship between various neurotransmitters and breast cancer cell growth has revealed their likely centrality to improving breast cancer treatment. Neurotransmitters play a key role in breast cancer biology through their effects on the cell cycle, epithelial mesenchymal transition, angiogenesis, in ammation, the tumor microenvironment and other pathways. Neurotransmitters and their receptors are vital to the initiation, progression and drug resistance of cancer and progress in our Biological understanding may point the way to lower-cost and lower-risk antitumor therapeutic strategies. This review discusses multiple neurotransmitters in the context of breast cancer. It also discusses risk factors, repurposing of pharmaceuticals impacting neurotransmitter pathways, and the opportunity for better integrated models that encompass exercise, the intestinal microbiome, and other non-pharmacologic considerations. Neurotransmitters’ role in breast cancer should no longer be ignored; it may appear to complicate the molecular picture but the ubiquity of neurotransmitters and their wide-ranging impacts provide an organizing framework upon which further understanding and progress against breast cancer can be based.

– Neurotransmitters appear to complicate the clinical and mechanistic picture of breast cancer, but denying this complexity is unlikely to pay dividends. Taking a signaling oriented view of breast cancer, particularly incorporating neurotransmitters, unifies various observations and provides clear direction for obtaining clinically significant short-term and long-term results in improving therapeutic strategies.

October 23, 2023 – Cancer neuroscience is emerging as an innovative field of research in oncology with a potential to identify novel therapeutic targets in the tumour microenvironment (TME). This is particularly relevant for colorectal cancer (CRC) given the unique role of the brain–gut axis (BGA) in GI physiology and pathology. The increasing attention on the essential role of the TME in cancer has shed light on the complex contribution provided by neural mediators to CRC growth and progression. Notably, targeting tumor neurotransmitter signaling and neurotrophic factors in the TME holds promise to be effective alone or in combination with targeted therapies. In fact, a close connection between neural signaling molecules and known druggable cancer-related pathways has been established, particularly angiogenesis, RAS/MAPK signaling and immunomodulation. Therefore, pharmacological manipulation of neurotransmitter pathways may improve the efficacy of existing targeted treatments.

January 18 2023 -Mutational analysis of microsatellite-stable gastrointestinal cancer with high tumour mutational burden; a retrospective cohort study. Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. This research aims to characterize molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours. Study confirmed that not all mutations related to TMB-H can enhance antri-tumour immune response. More composite biomarkers should be investigated (eg. mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provides novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1. 

March 2023 -This study explored the association and impact of genetic variants SNPs in the lipid metabolism pathway on progression-free survival and clinical outcomes in metastatic colorectal cancer patients receiving bevacizumab-based first-line treatment, using genetic and clinical data from FOLFIRI-bevacizumab cohorts in randomised trials, a retrospective analysis of FIRE-3 and MAVERICC trials. Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment.

In January 31, 2022 -WunderGlo Director Dr. Heinz-Josef Lenz was named one of the Top Doctors of Oncology in 2022 by The L.A. Business Journal. April 1, 2022 Dr. Heinz-Josef Lenz appointed as the inaugural Deputy Director for Research Programs at USC Norris Comprehensive Cancer Center. On November  21, 2022: WunderGlo Director Heinz-Josef named one of the top distinguished researchers in the world, recognized for his laboratory’s high quality research and the impact he is making across the scientific community (and he is the only physician on this list). 

Build up your muscles in the fight against cancer! – Dr Lenz’s team of colorectal cancer researchers have identified a metabolic pathway which is responsible for muscle build up but also for immune cell response in tumors. Modifying genes involved in this nucleotide pathway significantly changes the sensitivity of immune therapies and activates critical immune cells in the tumor microenvironment. Early collaborations show that immune cells communicate through a sophisticated system with cancer cells, allowing them to migrate, spread, and settle at unique spots in the body such as the liver – dependent on the communication pathways. Data from this unique and extensive collaboration between Dr. Lenz and experts in neuroscience and the tumor micro-environment – brings hope of leading to novel prevention and treatment strategies for colorectal cancer.

Dr Lenz’s team and colorectal cancer researchers throughout the world have identified that Circadian Rhythm predicts outcomes in colon cancer. They have characterized all critical genes in the regulation of the clock in tumor cells and have made significant progress in “Clocking the Tumor” –  meaning that they can treat with novel agents to put the clock  – back into the tumor cells. They have seen in cell-lines and mouse models – that they can kill colon cancer cells very effectively in tumors that are sensitive to immunotherapies. Their compounds are AS effective – and may be even more effective than the approved immunotherapies. -And these treatments can be taken orally by mouth – with very little side effects. 

Parkinson’s Nerve Colon Cancer Project: Dr. Lenz was one of the first to find that patients with Parkinson’s Disease seem to be protected against colon cancer. His group extensively studied the impact of Parkinson Signaling with the outcome in colorectal cancer patients and they found that Parkinson genes are significantly associated with the efficacy of chemotherapy & targeted antibodies in patients with metastatic disease. Very little is known about the connection of the nervous system and cancer cells. But when collaborations began with neuroscientists at USC, it became clear that other neuro-degenerative diseases are also related to colon cancer outcomes. Early collaborations show that nerve cells communicate through a sophisticated system with cancer cells, allowing them to migrate, spread, and settle at very unique spots in the body such as the liver – dependent on the communication pathways between nerve cells and colon cancer cells. Data from this unique and extensive collaboration in neuroscience and the tumor micro-environment – will potentially lead to novel prevention and treatment strategies for colorectal cancer.

March 2020 – Dr. Heinz-Josef Lenz Baricitinib Clinical Trial receives FDA Approval- the first Covid Trial at USC Norris – Dr. Lenz’s tireless work and dedicated lab research – brought amazing insights through a repurposed drug treatment discovery for Covid-19 – that received FDA approval – with the purpose of protecting major organs from damage by the virus, especially to the lungs & kidneys.

The Circadian Clock Protein Research Project suggests that genetic variations in the dopamine signaling pathway might indicate how a patient with advanced colorectal cancer would respond to treatment. The dopamine signaling pathway is part of what researchers call the Brain-Gut Axis, which is a line of communication between the brain and gut to regulate digestive function. Regarding colon cancer, “clock proteins” are shown to be associated with a bad prognosis. For example, night shift workers/flight attendants have higher risk of colon cancer, as this regulation of night/day is based on clock proteins. Our research is showing that Interference with clock proteins in cancer is showing promising anti-tumor effects.

Powerpoint Presentation Update on Molecular Targeted Therapies for Metastatic Colorectal Cancer by Dr. Heinz-Josef Lenz presented at GI ASCO San Francisco – January 2020.

On Tuesday, April 21st, 2020 WunderGlo Foundation Director, Dr. Heinz-Josef Lenz, MD, presented abstract research data: Molecular Landscape of Metastatic Colorectal Cancer – during Grand Rounds at USC Norris Comprehensive Cancer Center. Recent biomarker research in colorectal cancer has been remarkably progressed and assisted early drug development, especially molecular targeting agents in colon cancer. To evaluate the true value of a candidate or approved biomarker, the timing of testing and change of characterization by tumor environment such as previous treatment should be always considered when choosing patients and deciding treatment strategy. Liquid biopsy will become a standard method to non-invasively monitor dynamic changes in tumor genome during treatment that provides us better understanding about decision-making in the treatment of cancer patients. New classification such as CMS will be integrated in prospective clinical trials and hopefully speed up identification of novel therapies depending on activated pathways. Recent data showing promising results using NGS in patients with mCRC.

August 2020: In the News: WunderGlo Director, Dr. Heinz-Josef Lenz explains the exciting insight on the therapeutic approaches that are shaking up Third-Line Treatments for colorectal cancer patients. A wave of novel third-line therapeutic options have shown promising efficacy in patients with colorectal cancer (CRC), according to Heinz-Josef Lenz, MD, FACP, and refined technologies capable of detecting circulating tumor DNA (ctDNA) have opened the door to novel targets and a stronger understanding of disease biology, allowing for more informed treatment decisions. “In the third-line treatment setting for metastatic CRC, we are relying on the molecular subtyping of this disease because we understand that colon cancer is not just 1 disease. We already use the RAS mutation and we now use specific treatments for BRAFmutations,” said Lenz. “Another very interesting and important subgroup is those with HER2 overexpression and/or amplification. Several clinical trials [are examining] compounds [that are] showing very promising and exciting efficacy in this patient population.”

Most Colorectal cancers have spread before diagnosis when the initial tumor is detected, according to a new Stanford study of nearly 3,000 patients by researchers at the Stanford University, led by The Wunder Project Member, Dr. Christina Curtis.  Study emphasizes that Identifying patients in whom early metastasis is likely could better guide treatment decisions.The research was supported by the National Institutes of Health (grant DP1-CA238296), the American Cancer Society, the Wunderglo Foundation, the Emerson Collective Cancer Research Fund, the Innovative Genomics Initiative and the National Cancer Institute.