Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy?

Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.

Partial hepatectomy accelerates colorectal metastasis by priming an inflammatory premetastatic niche in the liver.

Background: Resection of colorectal liver metastasis is the standard of care for patients with Stage IV CRC. Despite undoubtedly improving the overall survival of patients, pHx for colorectal liver metastasis frequently leads to disease recurrence. The contribution of this procedure to metastatic colorectal cancer at a molecular level is poorly understood. We designed a mouse model of orthograde metastatic colorectal cancer (CRC) to investigate the effect of partial hepatectomy (pHx) on tumor progression. Methods: CRC organoids were implanted into the cecal walls of wild type mice, and animals were screened for liver metastasis. At the time of metastasis, 1/3 partial hepatectomy was performed and the tumor burden was assessed longitudinally using MRI. After euthanasia, different tissues were analyzed for immunological and transcriptional changes using FACS, qPCR, RNA sequencing, and immunohistochemistry. Results: Mice that underwent pHx presented significant liver hypertrophy and an increased overall metastatic load compared with SHAM operated mice in MRI. Elevation in the metastatic volume was defined by an increase in de novo liver metastasis without any effect on the growth of each metastasis. Concordantly, the livers of pHx mice were characterized by neutrophil and bacterial infiltration, inflammatory response, extracellular remodeling, and an increased abundance of tight junctions, resulting in the formation of a premetastatic niche, thus facilitating metastatic seeding. Conclusions: Regenerative pathways following pHx accelerate colorectal metastasis to the liver by priming a premetastatic niche.

Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation.

Hyperactivation of the RAS-RAF-MEK-ERK cascade - a mitogen-activated protein kinase pathway - has a well-known association with oncogenesis of leading tumor entities, including non-small cell lung cancer, colorectal carcinoma, pancreatic ductal adenocarcinoma, and malignant melanoma. Increasing evidence shows that genetic alterations leading to RAS-RAF-MEK-ERK pathway hyperactivation mediate contact- and soluble-dependent crosstalk between tumor, tumor microenvironment (TME) and the immune system resulting in immune escape mechanisms and establishment of a tumor-sustaining environment. Consequently, pharmacological interruption of this pathway not only leads to tumor-cell intrinsic disruptive effects but also modification of the TME and anti-tumor immunomodulation. At the same time, the importance of ERK signaling in immune cell physiology and potentiation of anti-tumor immune responses through ERK signaling inhibition within immune cell subsets has received growing appreciation. Specifically, a strong case was made for targeted MEK inhibition due to promising associated immune cell intrinsic modulatory effects. However, the successful transition of therapeutic agents interrupting RAS-RAF-MEK-ERK hyperactivation is still being hampered by significant limitations regarding durable efficacy, therapy resistance and toxicity. We here collate and summarize the multifaceted role of RAS-RAF-MEK-ERK signaling in physiology and oncoimmunology and outline the rationale and concepts for exploitation of immunomodulatory properties of RAS-RAF-MEK-ERK inhibition while accentuating the role of MEK inhibition in combinatorial and intermittent anticancer therapy. Furthermore, we point out the extensive scientific efforts dedicated to overcoming the challenges encountered during the clinical transition of various therapeutic agents in the search for the most effective and safe patient- and tumor-tailored treatment approach.

The Role of Immune Checkpoint Molecules for Relapse After Allogeneic Hematopoietic Cell Transplantation.

Immune checkpoint molecules represent physiological brakes of the immune system that are essential for the maintenance of immune homeostasis and prevention of autoimmunity. By inhibiting these negative regulators of the immune response, immune checkpoint blockade can increase anti-tumor immunity, but has been primarily successful in solid cancer therapy and Hodgkin lymphoma so far. Allogeneic hematopoietic cell transplantation (allo-HCT) is a well-established cellular immunotherapy option with the potential to cure hematological cancers, but relapse remains a major obstacle. Relapse after allo-HCT is mainly thought to be attributable to loss of the graft-versus-leukemia (GVL) effect and hence escape of tumor cells from the allogeneic immune response. One potential mechanism of immune escape from the GVL effect is the inhibition of allogeneic T cells via engagement of inhibitory receptors on their surface including PD-1, CTLA-4, TIM3, and others. This review provides an overview of current evidence for a role of immune checkpoint molecules for relapse and its treatment after allo-HCT, as well as discussion of the immune mediated side effect graft-vs.-host disease. We discuss the expression of different immune checkpoint molecules on leukemia cells and T cells in patients undergoing allo-HCT. Furthermore, we review mechanistic insights gained from preclinical studies and summarize clinical trials assessing immune checkpoint blockade for relapse after allo-HCT.

Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers with a dismal prognosis for the patient. This is due to limited diagnostic options for the early detection of the disease as well as its rather aggressive nature. Despite major advances in oncologic research in general, the treatment options in the clinic for PDAC have only undergone minor changes in the last decades. One major treatment advance would be the successful targeting of the oncogenic driver KRASmut. In the past, the indirect targeting of KRAS has been exploited, e. g., via upstream inhibition of receptor tyrosine kinases or via downstream MEK or PI3K inhibition. However, the experience gained from clinical trials and from the clinic itself in the treatment of KRASmut cancer entities has dampened the initial euphoria. Lately, with the development of KRASG12C-specific inhibitors, not only the direct but also the indirect targeting of KRASmut has gained momentum again. Though preclinical studies and preliminary early clinical studies of monotherapies have shown promising results, they have been overshadowed by the swift development of resistances resulting in inconsistent responses in patient cohorts. Currently, several different combination therapies for KRASmut cancer are being explored. If they hold the promise they have made in preclinical studies, they might also be suitable treatment options for patients suffering from PDAC.

ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage.

Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576-90. ©2017 AACR.