Resistance Mechanisms to Novel Therapies in Myeloma

The number of novel therapies for the treatment of multiple myeloma (MM) is rapidly increasing with proteasome inhibitors, immunomodulatory agents and monoclonal antibodies being the most well-known therapeutic classes whilst histone deacetylase inhibitors, selective inhibitors of nuclear export and CAR-T cells amongst others also being actively investigated. However, in parallel with the development and application of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibitors, particularly Bortezomib, class effects do not universally apply to all proteasome inhibitors, and within-class differences in efficacy, toxicity and resistance mechanisms have been observed. Immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression and its pathway components. However, the cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within-class differences in clinical efficacy and resistance patterns. Despite the progressive biological elucidation of resistance mechanisms to these novel therapies, attempts to specifically exploit these processes lag considerably behind and until such approaches become available, resistance to these therapies will remain a concern

Disparate In Vivo Efficacy of FTY720 in Xenograft Models of Philadelphia Positive and Negative B-lineage Acute Lymphoblastic Leukemia

Most patients with acute lymphoblastic leukemia (ALL) respond well to standard chemotherapy-based treatments. However a significant proportion of patients, particularly adult patients, relapse with the majority dying of leukemia. FTY720 is an immunosuppressive drug that was recently approved for the treatment of multiple sclerosis and is currently under pre-clinical investigation as a therapy for a number of hematological malignancies. Using human ALL xenografts in NOD/SCIDγc−/− mice, we show for the first time that three Ph+ human ALL xenografts responded to FTY720 with an 80±12% (p = 0.048) reduction in overall disease when treatment was commenced early. In contrast, treatment of mice with FTY720 did not result in reduced leukemia compared to controls using four separate human Ph− ALL xenografts. Although FTY720 reactivated PP2A in vitro, this reactivation was not required for death of Ph− ALL cells. The plasma levels of FTY720 achieved in the mice were in the high nanomolar range. However, the response seen in the Ph+ ALL xenografts when treatment was initiated early implies that in vivo efficacy may be obtained with substantially lower drug concentrations than those required in vitro. Our data suggest that while FTY720 may have potential as a treatment for Ph+ ALL it will not be a useful agent for the treatment of Ph− B-ALL

Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies

Facts • Efficacy of many chemotherapeutics and targeted therapies is dictated by cellular ceramide levels. • Oncogene activation skews sphingolipid metabolism to favour the production of pro-survival sphingolipids. • Inhibitors of enzymes involved in ceramide metabolism exhibit promise in the relapsed-refractory setting. • Anti-cancer activity of sphingosine kinase inhibitors provides several options for new drug combinations. Open Questions • What other clinically utilised drugs rely on increases in ceramide levels for their efficacy and can they be effectively partnered with other ceramide inducing agents? • How does ceramide modulate the Bcl-2 family proteins, Mcl-1 and Bcl-2? • Are sphingolipid enzyme inhibitors best suited in the frontline or relapsed-refractory setting

Induction of cell death <i>in vitro</i> of the indicated xenograft cells.

<p>ALL cells recovered from the spleens of untreated mice were cultured with the indicated concentrations of FTY720 for 16 hours and viability assessed by flow cytometry using annexin V and propidium iodide staining. The viability of cells in control cultures was 42% for xenograft 1345, 90% for xenograft 1999, 93% for xenograft 0398, 51% for xenograft ALL-3, 63% for xenograft ALL-55 and 34% for ALL-56.</p

Studies of FTY720 in hematological malignancies.

<p>ND - Not determined. <i>In vitro</i> IC₅₀ values were assessed at 24 hours unless otherwise indicated. FTY720 was administered by the intra-peritoneal route in all <i>in vivo</i> studies. Cell lines used for <i>in vivo</i> studies are indicated.</p